The present application claims the benefit of U.S. Provisional Application No.

63/123,353, filed December 9, 2020, and U.S. Provisional Application No. 63/169,495, filed April 1, 2021, the entirety of each of which is incorporated by reference herein.

FIELD OF INVENTION

The present invention is related to a chemical compound; an inhibitor of prostate specific membrane antigen (PSMA); a composition comprising the compound or inhibitor, respectively; the compound, the inhibitor or the composition, respectively, for use in a method for the diagnosis of a disease; the compound, the inhibitor or the composition, respectively, for use in a method for the treatment of a disease; the compound, the inhibitor or the composition, respectively, for use in a method of diagnosis and treatment of a disease which is also referred to as “thera(g)nosis” or “thera(g)nostics”; the compound, the inhibitor or the composition, respectively, for use in a method for delivering an effector to a PSMA expressing tissue; a method for the diagnosis of a disease using the compound, the inhibitor or the composition, respectively; a method for the treatment of a disease using the compound, the inhibitor or the composition, respectively; a method for the diagnosis and treatment of a disease which is also referred to as “thera(g)nosis” or “thera(g)nostics, using the compound, the inhibitor or the composition, respectively; a method for the delivery of an effector to a PSMA expressing tissue using the compound, the inhibitor or the composition, respectively.

BACKGROUND

Prostate cancer (PCa) is one of the most frequently diagnosed cancers in men, and is the second most common cause of cancer-related death after lung cancer. The risk of developing prostate cancer increases dramatically with age, particularly for men over 50. With an aging population and increases in life expectancy that have marked the last thirty years, the incidence rate of prostate cancer in the United States is approaching one in six men.

Early diagnosis and successful treatment of prostate cancer continues to be a major clinical challenge. Apart from new technologies that accurately detect prostatic lesions, understanding significant molecular cascades during prostate carcinogenesis, metastasis, and drug resistance are critical for the development of new therapeutic agents and intervention strategies. A molecular prostate cancer hallmark is the aberrant expression of the transmembrane glycoprotein prostate specific membrane antigen (PSMA) at the plasma membrane of almost every prostatic neoplasia. PSMA’s expression profile on prostate cancers and its enzymatic activity suggest that it might play an important role in prostate cancer and is amenable to pharmacological interventions. The ability to modulate PSMA levels and PSMA’s enzymatic activity could be useful in the treatment of cancer and other diseases and conditions mediated by PSMA.

PSMA is a trans-membrane, 750 amino acid type II glycoprotein (SEQ ID NO: 1) that has abundant and restricted expression on the surface of PCa, particularly in androgen-independent, advanced and metastatic disease. The latter is important since almost all PCa become androgen independent over time. PSMA possesses the criteria of a promising target for therapy, i.e., abundant and restricted (to prostate) expression at all stages of the disease, presentation at the cell surface but not shed into the circulation, and association with enzymatic or signaling activity. Metastatic spread and disease progression under androgen deprivation therapy signify the onset of metastatic castration resistant prostate cancer (mCRPC) - the lethal form of the disease, which severely deteriorates the quality of life of patients. Although therapies are approved for mCRPC, their survival benefit is generally limited to less than 6 months.

PSMA is also present in the neovasculature of solid tumors including kidney, lung, stomach, colon, and breast. Expression of PSMA is associated with the neovascular endothelium in nonprostate tumors.

The selective targeting of cancer cells with radiopharmaceuticals, either for imaging or therapeutic purposes is challenging. A variety of radionuclides are known to be useful for radioimaging or cancer radiotherapy. Compounds containing a glutamate-urea-glutamate (GUG) or a glutamate-urea-lysine (GUL) recognition element linked to a radionuclide-ligand conjugate are known to exhibit affinity for PSMA. A review on such PSMA targeting compounds states, “Originally, efforts regarding extensive structure-activity relationships were aimed at identifying permissible substitutions of the terminal glutamate that would improve the physicochemical and biologic characteristics of target ligands. However, all such substitutions reported to date have failed to provide viable leads and instead have resulted in compounds with substantially lower PSMA affinities” (Kopka et al., J Nucl Med 2017; 58:17S-26S).

Despite the significant advancement in the diagnosis and treatment of cancer, improved therapies are still being sought. There is a clinical need for improved therapies for the treatment of cancer, such as prostate cancer, including therapies which can provide a more effective and/or sustained response.

SUMMARY OF THE INVENTION

One aspect of the present disclosure pertains a compound of Formula 1

Formula 1, wherein

R is H or an effector domain which optionally comprises a linker.

Another aspect of the present disclosure pertains to a compound of Formula 2

Formula 2.

Another aspect of the present disclosure pertains to a compound of Formula 1 or Formula 2, wherein the linker is L- Y and the compound is a compound of Formula 3

Formula 3, wherein:

Y is an aromatic amino acid, preferably an aromatic a-amino acid, and preferably a structure selected from the group of Formula 4, 5, 6, 7, and 8, wherein the amino group of Y is covalently bound to L and the carbonyl group of Y is covalently bound to nitrogen as shown in Formula 3:

Formula 4 Formula 5 Formula 6 Formula 7 Formula 8;

L is an optional element, which covalently is mediating a linkage of the effector domain with Y, preferably L is an amino acid wherein its carboxyl group and the amino group are separated by at least two atoms, preferably the amino acid contains a carbocycle or a heterocycle and the carboxyl group and the amino group are separated by at least four atoms, and preferably the structure of the amino acid is selected from the group consisting of

Formula 9, 10, 11, 12, and 13:

Formula 9 Formula 10 Formula 11 Formula 12 Formula 13.

Another aspect of the present disclosure pertains to a compound of Formula 14

Formula 14.

Another aspect of the present disclosure pertains to a compound of Formula 18

Formula 18.

Another aspect of the present disclosure pertains to a compound of Formula 24 (PSM-01)

Formula 24.

Another aspect of the present disclosure pertains to a compound of Formula 25 (PSM-05)

Formula 25.

Another aspect of the present disclosure pertains to a compound of Formula 26 (PSM-06)

Formula 26.

Another aspect of the present disclosure pertains to a compound of Formula 27 (PSM-07)

Formula 27.

Another aspect of the present disclosure pertains to a compound of Formula 28 (PSM-08)

Formula 28.

Another aspect of the present disclosure pertains to a compound of Formula 1, Formula 2, Formula 3, Formula 14, Formula 18, Formula 24, Formula 25, Formula 26, Formula 27, or Formula 28, wherein the compound comprises a diagnostically active nuclide or a therapeutically active nuclide.

Another aspect of the present disclosure pertains to a method for the treatment of a disease in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to the disclosure. For example, such compounds may be compounds of Formula 1, Formula 2, Formula 3, Formula 14, Formula 18, Formula 24, Formula 25, Formula 26, Formula 27, or Formula 28.

It will be appreciated by a person skilled in the art that the problem underlying the present invention is solved by the subject matter of the attached independent claims; preferred embodiments may be taken from the attached dependent claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description, given by way of example, but not intended to limit the invention, is further illustrated by reference to the following figures from which further features, embodiments and advantages, may be taken. Figure 1. Synthesis scheme: solid phase synthesis of PSM-01.

Figure 2: Representative blank corrected sensorgram for compound PSM-01. Blank and reference cell corrected response (RU, Response Unit) data is shown as gray line. Fitted curve shown as dotted black line.

Figure 3: Representative radiochromatogram of ^{i n} In-PSM-01 with all peaks labeled with their retention times.

Figure 4: Graph depicting the percentage of injected dose per gram of tissue uptake (mean %ID/g, error bars indicate standard deviation) in the kidneys, liver, bloodpool and LNCaP as well as PC-3-PSMA tumors as determined by SPECT imaging of ⁿⁱ In-PSM-01 at 1 h, 4 h and 24 h post injection into the mouse model.

Figure 5: Exemplary SPECT/CT image of ^{i n} In-PSM-01 24 h post injection into one mouse with LNCaP and PC-3-PSMA tumors.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure relates to novel compounds suitable for use as diagnostic agents and/or pharmaceutical agents, for the diagnosis and/or treatment of prostate cancer and other diseases and conditions mediated by PSMA. The present disclosure provides novel compounds, capable of interacting with PSMA, that can deliver an effector, which can provide for the detection, treatment, and/or management of various diseases associated with one or more PSMA expressing tumors or cells, including prostate cancer.

The present disclosure is based on the surprising finding that the compounds of the disclosure provide for highly specific and potent binding to PSMA. These compounds contain a novel PSMA binding domain, including a quisqualic acid-urea-lysine domain, which is able to interact with PSMA and achieve improved binding affinity and other properties as described herein.

The compounds of the disclosure have one or more improved properties, including but not limited to, rapid tumor uptake, prolonged tumor retention, rapid clearance of the compound from non-tumor tissues, improved efficacy, and/or favorable biodistribution properties, with improved toxicity and side effect profiles. In an embodiment and as preferably used herein, a compound shows rapid tumor uptake if, within one hour after administration of the compound to a subject with a tumor, at least 0.1 % of the amount of the compound administered to the subject is taken up by the tumor; such tumor uptake is preferably determined by nuclear imaging.

For effective clinical utilization, PSMA inhibitor selection should be based, for example, on rapid uptake and persistent localization at the target site, with negligible retention in nontargeted tissues. Low levels of endogenous PSMA expression have also been found in organs such as normal prostate, proximal tubules of the kidneys, the lacrimal and salivary glands, the spleen, the liver, the intestinal membranes, the testes, the ovaries, and the brain (Chakravarty, et al 2018 Am J Nucl Med Mol Imaging, 8(4): 247-267), which insofar constitute non-target tissues.

For diagnosis and/or treatment, compounds of the disclosure can be complexed with radionuclides that are a-emitters, P-emitters, or y-emitters. Radionuclides that are a-emitters are capable of destroying tumors while causing very limited damage to the surrounding healthy tissue due to the short penetration depth of a particles. Their high linear energy transfer (LET) gives them an increased relative biological effectiveness (RBE) as compared to other radionuclide therapies. Furthermore, when a-emitting radionuclides are targeted to specific tumor cells in the body, they can be very effective in destroying metastases, which are difficult to treat by currently employed techniques (de Kruijff et al, 2015 Pharmaceuticals, 8, 321-336). However, toxicity is a primary limitation of the use of a-emitters.

Irradiation of salivary glands is reported to be the main dose-limiting side effect of therapeutic PSMA-inhibitors, especially when using a-emitters, particularly due to the irreversible nature of the xerostomia.

In the clinic, treatment with an effector, such as ²²⁵ Ac, complexed to a PSMA inhibitor has been shown to result in irreversible, grade 3/4 xerostomia leading to a significant impairment of the patients’ quality of life and thus represents a dose-limiting side effect for therapeutic use of a -emitting small molecule PSMA inhibitors (Tonnesmann et al, 2019, Pharmaceuticals 12, 18). PSMA-targeting antibodies, however, have shown no significant uptake in salivary glands. While the salivary glands are known to possess low levels of PSMA, the detected salivary gland uptake of PSMA-inhibitors in clinical studies does not correlate with the relatively low physiological PSMA-expression in that tissue, meaning the binding to the salivary gland is largely non-specific (Tonnesmann et al, 2019).

The PSMA inhibitors disclosed herein are surprisingly suitable as carriers for a-emitters for therapy because they can provide for effective treatment of diseases associated with one or more PSMA expressing tumors or cells, including prostate cancer, with reduced salivary gland uptake. This makes it possible to administer such compounds in higher doses, potentially resulting in improved response rates and better tumor control.

The compounds of the disclosure, including due to the presence of their novel PSMA binding domain, which includes a quisqualic acid-urea-lysine domain, have a favorable uptake ratio of tumor to non-tumor tissue (e.g., salivary glands, kidneys, or other non-tumor tissues). In an embodiment, and as preferably used herein, a quisqualic acid-urea-lysine domain is a moiety in which the amino group of the quisqualic acid moiety is covalently bound to a carbonyl group, and this carbonyl group is also covalently bound to the a-amino group of the lysine moiety. In a further embodiment, an example of a quisqualic acid-urea-lysine domain is shown in a box below with reference to Formula 3:

In certain embodiments, the favorable tumor to non-tumor tissue uptake of the present compounds allows delivery of a radioactive nuclide at a dose that could reduce tumor growth, or partially or completely destroy the tumor, while minimizing side effects. In certain embodiments, due to their favorable uptake ratio of tumor to non-tumor targets, compounds of the present disclosure surprisingly are able to overcome the unwanted side effect of severe xerostomia associated with PSMA-inhibitors. In certain embodiments, compounds of the present disclosure can advantageously provide for the effective treatment of diseases associated with one or more PSMA expressing tumors or cells, including prostate cancer, and may allow administration of higher doses, potentially resulting in improved response rates and better tumor control. In certain embodiments, compounds of the present disclosure can advantageously maximize therapeutic efficacy while minimizing negative side effects.

In some embodiments, compounds of the disclosure may advantageously be used in a method for the identification of a subject or a method for the selection of a subject from a group of subjects or the method for the stratification of a group of subjects, wherein the subject is likely to respond or likely not to respond to a treatment of a disease, wherein the method comprises carrying out a method of diagnosis using compounds according to the disclosure. In certain embodiments, such methods may advantageously optimize drug treatment, including minimizing risks and maximizing efficacy, for example by helping healthcare professionals identify subjects who might benefit the most from a given therapy and avoid unnecessary treatments.

The present disclosure is further described herein, including in the embodiments below.

Embodiment 1. A compound of Formula 1

Formula 1, wherein R is H or an effector domain which optionally comprises a linker.

Embodiment 2. The compound of Embodiment 1, wherein the compound is a compound of Formula 2

Formula 2.

Embodiment 3. The compound of Embodiment 1 or 2 wherein the linker is L-Y and the compound is a compound of Formula 3

Formula 3, wherein:

Y is an aromatic amino acid, preferably an aromatic a-amino acid and more preferably a structure selected from the group of Formula 4, 5, 6, 7, and 8, wherein the amino group of Y is covalently bound to L and the carbonyl group of Y is covalently bound to nitrogen as shown in Formula 3:

Formula 4 Formula 5 Formula 6 Formula 7 Formula 8; L is an optional element, which covalently is mediating a linkage of the effector domain with Y, preferably L is an amino acid wherein its carboxyl group and the amino group are separated by at least two atoms, more preferably the amino acid contains a carbocycle or a heterocycle and the carboxyl group and the amino group are separated by at least four atoms, and most preferably the structure of the amino acid is selected from the group consisting of Formula 9, 10, 11, 12, and 13:

Formula 9 Formula 10 Formula 11 Formula 12 Formula 13.

Embodiment 4. The compound of Embodiment 3, wherein L is of Formula 4, and Y is of Formula 9, and has the structure shown in Formula 14

Formula 14.

Embodiment 5. The compound of Embodiment 3, wherein -E-Y- is of Formula 15:

Formula 15.

Embodiment 6. The compound of Embodiment 5, wherein the compound is of Formula

Formula 16.

Embodiment 7. The compound of Embodiment 3 wherein -L-Y- is of Formula 17:

Formula 17.

Embodiment 8. The compound of Embodiment 7, wherein the compound is of Formula

Formula 18.

Embodiment 9. The compound of Embodiment 1, 2, 3, 4, 5, 6, 7, and 8, wherein the effector domain comprises a chelator.

Embodiment 10. The compound of Embodiment 9, wherein the chelator is selected from the group consisting of DOTA, DOTAGA, NOPO, PCTA, NOTA, NOD AGA, NODA- MPAA, HBED, TETA, CB-TE2A, DTPA, CHX-A“-DTPA, DFO, Macropa, Crown, DOTAM (also called TCMC), PSC, HOPO, HEHA, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, NxS4-x (N4, N2S2, N3S), Hynic, ^99m Tc(CO)3- chelators, and their analogs, more preferably DOTA, DOT AGA, NOPO, PCTA, DOTAM, PSC, Macropa, Crown, NOTA, NOD AGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, more preferably DOTA, DOT AGA, NOPO, PCTA, DOTAM, PSC, Macropa, Crown, NOTA, and NOD AGA; and most preferably DOTA, NOPO, PCTA, Macropa, and Crown.

Embodiment 11. The compound of Embodiments 9 and 10, wherein the compound is selected from the group consisting of Formula 19, Formula 20, Formula 21, Formula 22, and Formula 23:

Formula 19,

Formula 21,

Formula 23.

Embodiment 12. The compound of Formula 24 (PSM-01):

Formula 24.

Embodiment 13. The compound of Formula 25 (PSM-05)

Formula 25.

Embodiment 14. The compound of Formula 26 (PSM-06)

Formula 26.

Embodiment 15.

Formula 27.

Embodiment 16. The compound of Formula 28 (PSM-08)

Formula 28.

Embodiment 17. The compound of any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16, wherein the compound comprises a diagnostically active nuclide or a therapeutically active nuclide.

Embodiment 18. The compound of Embodiment 17, wherein the diagnostically active nuclide is a diagnostically active radionuclide.

Embodiment 19. The compound of Embodiment 18, wherein the diagnostically active radionuclide is selected from the group consisting of ⁴³ Sc, ⁴⁴ Sc, ⁵¹ Mn, ⁵² Mn, ⁶⁴ Cu, ⁶⁷ Ga, ⁶⁸ Ga, preferably ⁴³ Sc, ⁴⁴ Sc, ^Cu, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁸⁹ Zr, " ^m Tc, ⁱⁿ In, ¹⁵² Tb, ¹⁵⁵ Tb, ²⁰³ Pb, and more preferably ⁶⁴ Cu, ⁶⁸ Ga, and ⁿⁱ In.

Embodiment 20. The compound selected from the group consisting of the compounds of Formula 29 and Formula 30:

Formula 30 ( ⁶⁸ Ga-labeled PSM-01).

Embodiment 21. The compound of Formula 31 :

Formula 31 ( ⁶⁸ Ga-labeled PSM-05).

Embodiment 22. The compound of Embodiment 17, wherein the therapeutically active nuclide is a therapeutically active radionuclide.

Embodiment 23. The compound of Embodiment 22, wherein the therapeutically active radionuclide is selected from the group consisting of ⁴⁷ Sc, ⁶⁷ Cu, ⁸⁹ Sr, ⁹⁰ Y, ⁿⁱ In, ¹⁵³ Sm, ¹⁴⁹ Tb, ¹⁶¹ Tb, ¹⁷⁷ LU, ¹⁸⁶ Re, ¹⁸⁸ Re, ²¹² Pb, ²¹³ Bi, ²²³ Ra, ²²⁴ Ra, ²²⁵ Ac, ²²⁶ Th, ²²⁷ Th, ¹³¹ I, ²¹¹ At, preferably ⁴⁷ Sc, ⁶⁷ Cu, ⁹⁰ Y, ¹⁷⁷ LU, ¹⁸⁸ Re, ²¹² Pb, ²¹³ Bi, ²²⁵ Ac, ²²⁷ Th, and more preferably ⁹⁰ Y, ¹⁷⁷ Lu, ²¹² Pb, ²²⁵ Ac, and ²²⁷ Th.

Embodiment 24. The compound selected from the group consisting of the compounds of Formula 32, Formula 33 and Formula 34:

Formula 32 ( ²²⁵ Ac-labeled PSM-01),

Formula 34 ( ²¹² Pb-labeled PSM-01).

Embodiment 25. The compound of Formula 35:

Formula 35 ( ²²⁵ Ac-labeled PSM-06).

Embodiment 26. The compound of Formula 36:

Formula 36 ( ²¹² Pb-labeled PSM-07).

Embodiment 27. The compound of Embodiment 16, wherein the compound comprises a therapeutically active radionuclide that is ²¹² Pb ( ²¹² Pb-labeled PSM-08).

Embodiment28. The compound of any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 24, for use in a method for the diagnosis of a disease.

Embodiment 29. The compound of any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 20, 22, 23, 24, 25, 26, and 27, for use in a method for the treatment of a disease. Embodiment 30. The compound for use of Embodiments 28 and 29, wherein the disease is a disease involving the prostate specific membrane antigen (PSMA) protein.

Embodiment 31. The compound for use of any one of Embodiments 28, 29 and 30, wherein the disease involves cells showing upregulated expression of prostate specific membrane antigen (PSMA), preferably diseased tissue containing cells showing upregulated expression of PSMA.

Embodiment 32. The compound for use of any one of Embodiments 28, 29, 30, and 31, wherein the disease is a neoplasm, preferably a cancer or tumor.

Embodiment 33. The compound for use of Embodiment 32, wherein the tumor is selected from the group comprising an advanced tumor, a metastatic tumor, and a primary tumor.

Embodiment 34. The compound for use of Embodiment 32 and 33, wherein the tumor is selected from the group comprising a prostate tumor, a metastasized prostate tumor, a lung tumor, a renal tumor, a glioblastoma, a pancreatic tumor, a bladder tumor, a sarcoma, a melanoma, a breast tumor, a colon tumor, a pheochromocytoma, an esophageal tumor, a stomach tumor, a carcinoma, a squamous carcinoma (e.g., cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, and gullet), and an adenocarcinoma (e.g., prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, gullet, rectum, uterus, stomach, mammary gland, and ovary), and combinations thereof.

Embodiment 35. The compound for use of Embodiment 34, wherein the tumor is a prostate tumor or a metastasized prostate tumor.

Embodiment 36. The compound for use of Embodiment 32, wherein the cancer, is selected from the group comprising: prostate cancer (e.g., metastatic castration resistant prostate cancer), renal cancer (e.g., clear cell carcinoma), head cancer, neck cancer, head and neck cancer, lung cancer (e.g., non-small cell lung cancer), salivary gland cancer, breast cancer, colorectal cancer, esophageal cancer, stomach cancer, liver cancer (e.g., hepatocellular cancer), thyroid cancer, glioblastoma, glioma, gall bladder cancer, laryngeal cancer, leukemia/lymphoma, uterine cancer, skin cancer (e.g., melanoma), endocrine cancer, sarcoma, urinary cancer, pancreatic cancer, gastrointestinal cancer, ovarian cancer, cervical cancer, endometrial cancer, fallopian tube cancer, primary peritoneal cancer, hematological cancer (e.g., diffuse large B cell lymphoma, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, follicular lymphoma, acute myeloid leukemia, or multiple myeloma), cancer of unknown primary, adenomas, and tumor neovasculature.

Embodiment 37. The compound for use of Embodiment 36, wherein the cancer is prostate cancer.

Embodiment 38. The compound for use of any one of Embodiments 28, 30, 31, 32, 33, 34, 35, 36, and 37, wherein the compound comprises a diagnostically active nuclide, preferably a diagnostically active radionuclide.

Embodiment 39. The compound for use of Embodiment 38, wherein the diagnostically active nuclide is selected from the group comprising ⁴³ Sc, ^Sc, ⁵¹ Mn, ⁵² Mn, ⁶⁴ Cu, ⁶⁷ Ga, ⁶⁸ Ga, preferably ⁴³ Sc, ⁴⁴ Sc, ^Cu, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁸⁹ Zr, " ^m Tc, ⁱⁿ In, ¹⁵² Tb, ¹⁵⁵ Tb, ²⁰³ Pb, and more preferably ⁶⁴ Cu, ⁶⁸ Ga, and ⁿⁱ In.

Embodiment 40. The compound for use of any one of Embodiments 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, and 39, wherein the method for the diagnosis is an imaging method.

Embodiment 41. The compound for use of Embodiment 40, wherein the imaging method is selected from the group consisting of scintigraphy, Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), SPECT/computed tomography (CT), PET/CT, and combinations thereof.

Embodiment 42. The compound for use of any one of Embodiments 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, and 41, wherein the method comprises the administration of a diagnostically effective amount of the compound to a subject, preferably to a mammal, wherein the mammal is selected from the group comprising man, companion animals, pets, and livestock, more preferably the subject is selected from the group comprising man, dog, cat, horse, and cow, and most preferably the subject is a human being.

Embodiment 43. The compound for use of any one of Embodiments 29, 30, 31, 32, 33, 34, 35, 36, and 37, wherein the compound comprises a therapeutically active nuclide, preferably a therapeutically active radionuclide. Embodiment 44. The compound for use of Embodiment 43, wherein the therapeutically active nuclide is selected from the group comprising ⁴⁷ Sc, ⁶⁷ Cu, ⁸⁹ Sr, ⁹⁰ Y, ⁱⁿ In, ¹⁵³ Sm, ¹⁴⁹ Tb, ¹⁶¹ Tb, ¹⁷⁷ LU, ¹⁸⁶ Re, ¹⁸⁸ Re, ²¹² Pb, ²¹³ Bi, ²²³ Ra, ²²⁴ Ra, ²²⁵ Ac, ²²⁶ Th, ²²⁷ Th, ¹³¹ I, ²¹¹ At, preferably ⁴⁷ Sc, ⁶⁷ Cu, ⁹⁰ Y, ¹⁷⁷ LU, ¹⁸⁸ Re, ²¹² Pb, ²¹³ Bi, ²²⁵ Ac, ²²⁷ Th, and more preferably ⁹⁰ Y, ¹⁷⁷ Lu, ²¹² Pb, ²²⁵ Ac, and ²²⁷ Th.

Embodiment 45. The compound for use of any one of Embodiments 29, 30, 31, 32, 33, 34, 35, 36, 37, 43, and 44, wherein the method comprises the administration of a therapeutically effective amount of the compound to a subject, preferably to a mammal, wherein the mammal is selected from the group comprising man, companion animals, pets, and livestock, more preferably the subject is selected from the group comprising man, dog, cat, horse, and cow, and most preferably the subject is a human being.

Embodiment 46. The compound of any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 24, for use in a method for the identification of a subject, wherein the subject is likely to respond or likely not to respond to a treatment of a disease, wherein the method for the identification of a subject comprises carrying out a method of diagnosis using the compound of any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 24, preferably a method for the diagnosis of a disease as described in any one of Embodiments 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, and 42.

Embodiment 47. The compound of any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 24, for use in a method for the selection of a subject from a group of subjects, wherein the subject is likely to respond or likely not to respond to a treatment of a disease, wherein the method for the selection of a subject from a group of subjects comprises carrying out a method of diagnosis using the compound of any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 24, preferably a method for the diagnosis of a disease as described in any one of Embodiments 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, and 42.

Embodiment 48. The compound of any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 24, for use in a method for the stratification of a group of subjects into subjects which are likely to respond to a treatment of a disease, and into subjects which are not likely to respond to a treatment of a disease, wherein the method for the stratification of a group of subjects comprises carrying out a method of diagnosis using the compound of any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 24, preferably a method for the diagnosis of a disease as described in any one of Embodiments 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, and 42.

Embodiment 49. The compound for use of any one of Embodiments 46, 47, and 48, wherein the disease is a disease involving the prostate specific membrane antigen (PSMA) protein.

Embodiment 50. The compound for use of any one of Embodiments 46, 47, 48, and 49, wherein the disease involves cells showing upregulated expression of prostate specific membrane antigen (PSMA).

Embodiment 51. The compound for use of any one of Embodiments 46, 47, 48, 49 and 50, wherein the disease is a neoplasm, preferably a cancer or tumor.

Embodiment 52. The compound for use of Embodiment 51 , wherein the tumor is selected from the group comprising a prostate tumor, a metastasized prostate tumor, a lung tumor, a renal tumor, a glioblastoma, a pancreatic tumor, a bladder tumor, a sarcoma, a melanoma, a breast tumor, a colon tumor, a pheochromocytoma, an esophageal tumor, a stomach tumor, a carcinoma, a squamous carcinoma (e.g., cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, and gullet), and an adenocarcinoma (e.g., prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, gullet, rectum, uterus, stomach, mammary gland, and ovary), and combinations thereof.

Embodiment 53. The compound for use of Embodiment 52, wherein the tumor is a prostate tumor or a metastasized prostate tumor.

Embodiment 54. The compound for use of Embodiment 51, wherein the neoplasm, cancer, and tumor are each and individually selected from the group comprising prostate cancer (e.g., metastatic castration resistant prostate cancer), renal cancer (e.g., clear cell carcinoma), head cancer, neck cancer, head and neck cancer, lung cancer (e.g., non-small cell lung cancer), salivary gland cancer, breast cancer, colorectal cancer, esophageal cancer, stomach cancer, liver cancer (e.g., hepatocellular cancer), thyroid cancer, glioblastoma, glioma, gall bladder cancer, laryngeal cancer, leukemia/lymphoma, uterine cancer, skin cancer (e.g., melanoma), endocrine cancer, sarcoma, urinary cancer, pancreatic cancer, gastrointestinal cancer, ovarian cancer, cervical cancer, endometrial cancer, fallopian tube cancer, primary peritoneal cancer, hematological cancer (e.g., diffuse large B cell lymphoma, Hodgkin’s lymphoma, NonHodgkin’s lymphoma, follicular lymphoma, acute myeloid leukemia, or multiple myeloma), cancer of unknown primary, adenomas, and tumor neovasculature.

Embodiment 55. The compound for use of Embodiment 54, wherein the cancer is prostate cancer.

Embodiment 56. The compound for use of any one of Embodiments 46, 47, 48, 49, 50, 51, 52, 53, 54, and 55, wherein the method of diagnosis is an imaging method.

Embodiment 57. The compound for use of Embodiment 56 wherein the imaging method is selected from the group comprising scintigraphy, Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), SPECT/computed tomography (CT), PET/CT, and combinations thereof, and combinations thereof.

Embodiment 58. The compound for use of any one of Embodiments 46, 47, 48, 49, 50, 51, 52, 53, 54, and 55, wherein the compound comprises a diagnostically active nuclide, preferably a diagnostically active radionuclide.

Embodiment 59. The compound for use of Embodiment 58, wherein the diagnostically active nuclide is selected from the group comprising ⁴³ Sc, ^Sc, ⁵¹ Mn, ⁵² Mn, ⁶⁴ Cu, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁸⁹ Zr, ^94m Tc, " ^m Tc, ⁿⁱ In, ¹⁵² Tb, ¹⁵⁵ Tb, ¹⁷⁷ Lu, ^2O1 T1, ²⁰³ Pb, ¹⁸ F, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, and ¹²⁵ I, preferably ⁴³ Sc, ^Sc, ^Cu, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁸⁹ Zr, " ^m Tc, ^{i n} In, ¹⁵² Tb, ¹⁵⁵ Tb, and ²⁰³ Pb, and more preferably ⁶⁴ Cu, ⁶⁸ Ga, and ⁿⁱ In.

Embodiment 60. The compound of any one of Embodiments 1, 2, 3, 4, 5, 6, 7, and 8, for use in a method for delivering an effector to prostate specific membrane antigen (PSMA), wherein the effector is selected from the group comprising a diagnostically active agent and a therapeutically active agent.

Embodiment 61. The compound for use of Embodiment 60, wherein the effector is selected from the group comprising a diagnostically active nuclide and a therapeutically active nuclide. Embodiment 62. The compound for use of Embodiment 61, wherein the diagnostically active nuclide is a diagnostically active radionuclide.

Embodiment 63. The compound for use of Embodiment 62, wherein the diagnostically active radionuclide is selected from the group consisting of ⁴³ Sc, ^Sc, ⁵¹ Mn, ⁵² Mn, ⁶⁴ Cu, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁸⁹ Zr, ^94m Tc, " ^m Tc, ^{i n} In, ¹⁵² Tb, ¹⁵⁵ Tb, ¹⁷⁷ Lu, ^2O1 T1, ²⁰³ Pb, ¹⁸ F, ⁷⁶ Br, ⁷⁷ Br, ¹²³ 1, ¹²⁴ I, and ¹²⁵ I, preferably ⁴³ Sc, ^Sc, ⁶⁴ Cu, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁸⁹ Zr, " ^m Tc, ⁱⁿ In, ¹⁵² Tb, ¹⁵⁵ Tb, and ²⁰³ Pb, and more preferably ⁶⁴ Cu, ⁶⁸ Ga, and ^{i n} In.

Embodiment 64. The compound for use of any one of Embodiments 60, 61, 62, and 63, wherein the prostate specific membrane antigen (PSMA) is expressed by a cell, preferably a prostate cell, a metastasized prostate cell, a lung cell, a renal cell, a pancreatic cell, a bladder cell, a breast cell, a colon cell, a germ cell, an esophageal cell, a stomach cell, an endothelial cell and combinations thereof each showing upregulated expression of PSMA.

Embodiment 65. The compound for use of Embodiment 64, wherein the cell is contained in or part of a tissue, preferably a diseased tissue of a subject suffering from a disease.

Embodiment 66. The compound for use of Embodiment 65, wherein the disease involves cells showing upregulated expression of PSMA, preferably diseased tissue containing cells showing upregulated expression of PSMA.

Embodiment 67. The compound for use of any one of Embodiments 65 and 66, wherein the disease is a neoplasm, preferably a cancer or tumor.

Embodiment 68. The compound for use of Embodiment 67, wherein the tumor is selected from the group comprising a prostate tumor, a metastasized prostate tumor, a lung tumor, a renal tumor, a glioblastoma, a pancreatic tumor, a bladder tumor, a sarcoma, a melanoma, a breast tumor, a colon tumor, a pheochromocytoma, an esophageal tumor, a stomach tumor, a carcinoma, a squamous carcinoma (e.g., cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, and gullet), and an adenocarcinoma (e.g., prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, gullet, rectum, uterus, stomach, mammary gland, and ovary), and combinations thereof.

Embodiment 69. The compound for use of Embodiment 67, wherein the cancer is selected from the group comprising prostate cancer (e.g., metastatic castration resistant prostate cancer), renal cancer (e.g., clear cell carcinoma), head cancer, neck cancer, head and neck cancer, lung cancer (e.g., non-small cell lung cancer), salivary gland cancer, breast cancer, colorectal cancer, esophageal cancer, stomach cancer, liver cancer (e.g., hepatocellular cancer), thyroid cancer, glioblastoma, glioma, gall bladder cancer, laryngeal cancer, leukemia/lymphoma, uterine cancer, skin cancer (e.g., melanoma), endocrine cancer, sarcoma, urinary cancer, pancreatic cancer, gastrointestinal cancer, ovarian cancer, cervical cancer, endometrial cancer, fallopian tube cancer, primary peritoneal cancer, hematological cancer (e.g., diffuse large B cell lymphoma, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, follicular lymphoma, acute myeloid leukemia, or multiple myeloma), cancer of unknown primary, adenomas, and tumor neovasculature.

Embodiment 70. The compound for use of Embodiment 61, wherein the therapeutically active nuclide is a therapeutically active radionuclide.

Embodiment 71. The compound for use of Embodiment 70, wherein the therapeutically active radionuclide is selected from the group consisting of ⁴⁷ Sc, ⁶⁷ Cu, ⁸⁹ Sr, ⁹⁰ Y, ^{i n} In, ¹⁵³ Sm, ¹⁴⁹ Tb, ¹⁶¹ Tb, ¹⁷⁷ LU, ¹⁸⁶ Re, ¹⁸⁸ Re, ²¹² Pb, ²¹³ Bi, ²²³ Ra, ²²⁴ Ra, ²²⁵ Ac, ²²⁶ Th, ²²⁷ Th, ¹³¹ I, ²¹¹ At, preferably ⁴⁷ Sc, ⁶⁷ Cu, ⁹⁰ Y, ¹⁷⁷ Lu, ¹⁸⁸ Re, ²¹² Pb, ²¹³ Bi, ²²⁵ Ac, ²²⁷ Th, and more preferably ⁹⁰ Y, ¹⁷⁷ LU, ²¹² Pb, ²²⁵ Ac, and ²²⁷ Th.

Embodiment 72. The compound for use of any one of Embodiment 70 and 71, wherein the prostate specific membrane antigen (PSMA) is expressed by a cell, preferably a prostate cell, a metastasized prostate cell, a lung cell, a renal cell, a pancreatic cell, a bladder cell, a breast cell, a colon cell, a germ cell, an esophageal cell, a stomach cell, an endothelial cell and combinations thereof each showing upregulated expression of PSMA.

Embodiment 73. The compound for use of Embodiment 72, wherein the cell is contained in or part of a tissue, preferably a diseased tissue of a subject suffering from a disease.

Embodiment 74. The compound for use of Embodiment 73, wherein the disease involves cells showing upregulated expression of prostate specific membrane antigen (PSMA), preferably diseased tissue containing cells showing upregulated expression of PSMA.

Embodiment 75. The compound for use of any one of Embodiments 73 and 74, wherein the disease is a neoplasm, preferably a cancer or tumor. Embodiment 76. The compound for use of Embodiment 75, wherein the tumor is selected from the group comprising a prostate tumor, a metastasized prostate tumor, a lung tumor, a renal tumor, a glioblastoma, a pancreatic tumor, a bladder tumor, a sarcoma, a melanoma, a breast tumor, a colon tumor, a pheochromocytoma, an esophageal tumor, a stomach tumor, a carcinoma, a squamous carcinoma (e.g., cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, and gullet), and an adenocarcinoma (e.g., prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, gullet, rectum, uterus, stomach, mammary gland, and ovary), and combinations thereof.

Embodiment 77. The compound for use of Embodiment 75, wherein the cancer is selected from the group comprising prostate cancer (e.g., metastatic castration resistant prostate cancer), renal cancer (e.g., clear cell carcinoma), head cancer, neck cancer, head and neck cancer, lung cancer (e.g., non-small cell lung cancer), salivary gland cancer, breast cancer, colorectal cancer, esophageal cancer, stomach cancer, liver cancer (e.g., hepatocellular cancer), thyroid cancer, glioblastoma, glioma, gall bladder cancer, laryngeal cancer, leukemia/lymphoma, uterine cancer, skin cancer (e.g., melanoma), endocrine cancer, sarcoma, urinary cancer, pancreatic cancer, gastrointestinal cancer, ovarian cancer, cervical cancer, endometrial cancer, fallopian tube cancer, primary peritoneal cancer, hematological cancer (e.g., diffuse large B cell lymphoma, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, follicular lymphoma, acute myeloid leukemia, or multiple myeloma), cancer of unknown primary, adenomas, and tumor neovasculature.

Embodiment 78. The compound for use of Embodiment 68 and 76, wherein the tumor is a prostate tumor or a metastasized prostate tumor.

Embodiment 79. The compound for use of Embodiment 69 and 77, wherein the cancer is prostate cancer.

Embodiment 80. A composition, preferably a pharmaceutical composition, wherein the composition comprises a compound according to any one of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27, and a pharmaceutically acceptable excipient.

Embodiment 81. The composition of Embodiment 80 for use in any method as defined in any of the preceding embodiments. Embodiment 82. A method for the diagnosis of a disease in a subject, wherein the method comprises administering to the subject a diagnostically effective amount of a compound according to any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 24.

Embodiment 83. The method of Embodiment 82, wherein the compound comprises a diagnostically active agent, whereby the agent is preferably a diagnostically active radionuclide.

Embodiment 84. A method for the treatment of a disease in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to any one of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 20, 22, 23, 24, 25, 26, and 27.

Embodiment 85. The method of Embodiment 84, wherein the compound comprises a therapeutically active agent, whereby the agent is preferably a therapeutically active radionuclide.

Embodiment 86. The method of any one of Embodiments 82, 83, 84, and 85, wherein the disease is a disease involving the prostate specific membrane antigen (PSMA) protein.

Embodiment 87. The method of any one of Embodiments 82, 83, 84, 85, and 86, wherein the disease involves cells showing upregulated expression of prostate specific membrane antigen (PSMA), preferably diseased tissue containing cells showing upregulated expression of PSMA.

Embodiment 88. A kit comprising a compound according to any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27, one or more optional excipient(s) and optionally one or more device(s), whereby the device(s) is/are selected from the group comprising a labeling device, a purification device, a handling device, a radioprotection device, an analytical device or an administration device.

Embodiment 89. The kit of Embodiment 88 for use in any method as defined in any of the preceding Embodiments. It will be acknowledged by a person skilled in the art that a compound of the disclosure is any compound disclosed herein, including but not limited to any compound described in any of the above embodiments and any of the following embodiments.

It will be acknowledged by a person skilled in the art that a method of the disclosure is any method disclosed herein, including but not limited to any method described in any of the above embodiments and any of the following embodiments.

It will be acknowledged by a person skilled in the art that a composition of the disclosure is any composition disclosed herein, including but not limited to any composition described in any of the above embodiments and any of the following embodiments.

It will be acknowledged by a person skilled in the art that a kit of the disclosure is any kit disclosed herein, including but not limited to any kit described in any of the above embodiments and any of the following embodiments.

It will be acknowledged by a person skilled in the art that the expression “aspect of the disclosure” is used synonymously with the term “aspect of the invention” and, respectively, “aspect of the present invention”, and that the expression “embodiment of the disclosure” is used synonymously with the term “embodiment of the invention” and, respectively, “embodiment of the present invention”.

Except where otherwise indicated, all numbers expressing quantities of amounts, conditions, and so forth used in the disclosure are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present disclosure are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. At the very least, and not to be considered as an attempt to limit the application of the doctrine of equivalents, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding conventions.

Additionally, the disclosure of numerical ranges within the present disclosure is considered to be a disclosure of all numerical values and ranges within that range. For example, if a range is from 1 to 10, it is deemed to include, for example, 1, 2, 2.2, 3, 4, 5, 6, 7, 7.4, 7.6, 8, 8.7, 9, 9.5, 10, or any other value or range (integer or non-integer) within the range. Moreover, as used herein, the term “at least” includes the stated number, e.g., “at least 50” includes 50.

In an embodiment, and as preferably used herein, “(Ci-C8)alkyl” refers to a saturated or unsaturated, straight-chain or branched hydrocarbon group having from 1 to 8 carbon atoms. Representative (Ci-Cs)alkyl groups include, but are not limited to, any of methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methyl-butyl, 3- methyl-butyl, 3-pentyl, 3-methyl-but-2-yl, 2-methyl-but-2-yl, 2,2-dimethylpropyl, n-hexyl, 2- hexyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 3-hexyl, 2-ethyl-butyl, 2-methyl- pent-2-yl, 2,2-dimethyl-butyl, 3,3-dimethyl-butyl, 3-methyl-pent-2-yl, 4-methyl-pent-2-yl,

2.3-dimethyl-butyl, 3 -methyl-pent-3 -yl, 2-methyl-pent-3-yl, 2,3-dimethyl-but-2-yl, 3,3- dimethyl-but-2-yl, n-heptyl, 2-heptyl, 2-methyl-hexyl, 3-methyl-hexyl, 4-methyl-hexyl, 5- methyl-hexyl, 3-heptyl, 2-ethyl-pentyl, 3-ethyl-pentyl, 4-heptyl, 2-methyl-hex-2-yl, 2,2- dimetyhl-pentyl, 3,3-dimetyhl-pentyl, 4,4-dimetyhl-pentyl, 3-methyl-hex-2-yl, 4-methyl-hex-

2-yl, 5-methyl-hex-2-yl, 2,3-dimethyl-pentyl, 2,4-dimethyl-pentyl, 3,4-dimethyl-pentyl, 3- methyl-hex-3-yl, 2-ethyl-2-methyl-butyl, 4-methyl-hex-3-yl, 5-methyl-hex-3-yl, 2-ethyl-3- methyl-butyl, 2,3-dimethyl-pent-2-yl, 2,4-dimethyl-pent-2-yl, 3,3-dimethyl-pent-2-yl, 4,4- dimethyl-pent-2-yl, 2,2,3-trimethyl-butyl, 2,3,3-trimethyl-butyl, 2,3,3-trimethyl-but-2-yl, n- octyl, 2-octyl, 2-methyl-heptyl, 3-methyl-heptyl, 4-methyl-heptyl, 5-methyl-heptyl, 6-methyl- heptyl, 3-octyl, 2-ethyl-hexyl, 3-ethyl-hexyl, 4-ethyl-hexyl, 4-octyl, 2-propyl-pentyl, 2- methyl-hept-2-yl, 2,2-dimethyl-hexyl, 3,3-dimethyl-hexyl, 4,4-dimethyl-hexyl, 5,5-dimethyl- hexyl, 3-methyl-hept-2-yl, 4-methyl-hept-2-yl, 5-methyl-hept-2-yl, 6-methyl-hept-2-yl, 2,3- dimethyl-hex-l-yl, 2,4-dimethyl-hex-l-yl, 2,5-dimethyl-hex-l-yl, 3,4-dimethyl-hex-l-yl, 3,5- dimethyl-hex-l-yl, 3,5-dimethyl-hex-l-yl, 3-methyl-hept-3-yl, 2-ethyl-2-methyl-l-yl, 3-ethyl-

3 -methyl- 1-yl, 4-methyl-hept-3-yl, 5-methyl-hept-3-yl, 6-methyl-hept-3-yl, 2-ethyl-3 -methylpentyl, 2-ethyl-4-methyl-pentyl, 3-ethyl-4-methyl-pentyl, 2,3-dimethyl-hex-2-yl, 2,4- dimethyl-hex-2-yl, 2,5-dimethyl-hex-2-yl, 3,3-dimethyl-hex-2-yl, 3,4-dimethyl-hex-2-yl, 3,5- dimethyl-hex-2-yl, 4,4-dimethyl-hex-2-yl, 4,5-dimethyl-hex-2-yl, 5,5-dimethyl-hex-2-yl,

2.2.3-trimethyl-pentyl, 2,2,4-trimethyl-pentyl, 2,3,3-trimethyl-pentyl, 2,3,4-trimethyl-pentyl,

2.4.4-trimethyl-pentyl, 3,3,4-trimethyl-pentyl, 3,4,4-trimethyl-pentyl, 2,3,3-trimethyl-pent-2- yl, 2,3,4-trimethyl-pent-2-yl, 2,4,4-trimethyl-pent-2-yl, 3,4,4-trimethyl-pent-2-yl, 2, 2,3,3- tetramethyl-butyl, 3,4-dimethyl-hex-3-yl, 3,5-dimethyl-hex-3-yl, 4,4-dimethyl-hex-3-yl, 4,5- dimethyl-hex-3-yl, 5,5-dimethyl-hex-3-yl, 3-ethyl-3-methyl-pent-2-yl, 3-ethyl-4-methyl-pent- 2-yl, 3-ethyl-hex-3-yl, 2,2-diethyl-butyl, 3-ethyl-3-methyl-pentyl, 4-ethyl-hex-3-yl, 5-methyl- hept-3-yl, 2-ethyl-3-methyl-pentyl, 4-methyl-hept-4-yl, 3-methyl-hept-4-yl, 2-methyl-hept-4- yl, 3-ethyl-hex-2-yl, 2-ethyl-2-methyl-pentyl, 2-isopropyl-pentyl, 2,2-dimethyl-hex-3-yl, 2,2,4-trimethyl-pent-3-yl and 2-ethyl-3-methyl-pentyl. A (Ci-Cs)alkyl group can be unsubstituted or substituted with one or more groups, including, but not limited to, (Ci- C ₈ )alkyl, -O-[(Ci-C ₈ )alkyl], -aryl, -CO-R’, -O-CO-R’, -CO-OR’, -CO-NH ₂ , -CO-NHR’, -CO- NR’2, -NH-CO-R’, -SO2-R’, -SO-R’, -OH, -halogen, -N3, -NH ₂ , -NHR’, -NR’ 2 and -CN; where each R’ is independently selected from -(Ci-Cs)alkyl and aryl.

In an embodiment, and as preferably used herein, “carbocycle” refers to a saturated, unsaturated or aromatic mono- or bicyclic carbocyclic ring. A carbocycle can be unsubstituted or substituted with one or more groups, including, but not limited to, (Ci-Cs)alkyl, -O-[(Ci- C ₈ )alkyl], -aryl, -CO-R’, -O-CO-R’, -CO-OR’, -CO-NH2, -CO-NHR’, -CO-NR’2, -NH-CO-R’, -SO2-R’, -SO-R’, -OH, -halogen, -N3, -NH2, -NHR’, -NR’ 2 and -CN; where each R’ is independently selected from -(Ci-Cs)alkyl and aryl.

In an embodiment, and as preferably used herein, “heterocycle” refers to a saturated, unsaturated or aromatic mono- or bicyclic heterocyclic ring. A heterocycle group can be unsubstituted or substituted with one or more groups, including, but not limited to, (Ci- C ₈ )alkyl, -O-[(Ci-C ₈ )alkyl], -aryl, -CO-R’, -O-CO-R’, -CO-OR’, -CO-NH2, -CO-NHR’, -CO- NR’2, -NH-CO-R’, -SO2-R’, -SO-R’, -OH, -halogen, -N3, -NH ₂ , -NHR’, -NR’ 2 and -CN; where each R’ is independently selected from -(Ci-Cs)alkyl and aryl.

In an embodiment, and as preferably used herein, "aryl" refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

In an embodiment, and as preferably used herein, “heteroaryl” refers to a heterocyclic aromatic group. Examples of heteroaryl groups include, but are not limited to, furane, thiophene, pyridine, pyrimidine, benzothiophene, benzofurane, and quinoline.

In an embodiment, and as preferably used herein, “(C5-C6)heteroaryl” refers to a heterocyclic aromatic group consisting of 5 or 6 ring atoms wherein at least one atom is different from carbon, including, for example, nitrogen, sulfur or oxygen. A heterocyclic aromatic group can be unsubstituted or substituted with one or more groups including, but not limited to, -(Ci- C ₈ )alkyl, -O-[(Ci-C ₈ )alkyl], -aryl, -CO-R’, -O-CO-R’, -CO-OR’, -CO-NH2, -CO-NHR’, -CO- NR’ 2, -NH-CO-R’, -SO2-R’, -SO-R’, -OH, -halogen, -N3, -NH ₂ , -NHR’, -NR’ 2 and -CN; where each R’ is independently selected from -(Ci-Cs)alkyl and aryl.

In an embodiment, and as preferably used herein, atoms with unspecified atomic mass numbers in any structural formula or in any passage of the instant specification are either of unspecified isotopic composition, naturally occurring mixtures of isotopes or individual isotopes. This applies in particular to carbon, oxygen, nitrogen, sulfur, phosphorus, halogens and metal atoms, including but not limited to C, O, N, S, F, P, Cl, Br, At, Sc, Cr, Mn, Co, Fe, Cu, Ga, Sr, Zr, Y, Mo, Tc, Ru, Rh, Pd, Pt, Ag, In, Sb, Sn, Te, I, Pr, Pm, Dy, Sm, Gd, Tb, Ho, Dy, Er, Yb, Tm, Lu, Sn, Re, Rd, Os, Ir, Au, Pb, Bi, Po, Fr, Ra, Ac, Th, and Fm.

In an embodiment, and as preferably used herein, a “chelator” is a compound, which is capable of forming a chelate, whereby a chelate is a compound, including, for example, a cyclic compound where a metal or a moiety having an electron gap or a lone pair of electrons participates in the formation of the ring. In certain embodiments, a chelator is this kind of compound where a single ligand occupies more than one coordination site at a central atom.

In an embodiment, and as preferably used herein, a “diagnostically active compound” is a compound which is suitable for or useful in at least the diagnosis of a disease.

In an embodiment, and as preferably used herein, a “diagnostic agent” or a “diagnostically active agent” is a compound, which is suitable for or useful in at least the diagnosis of a disease.

In an embodiment, and as preferably used herein, a “diagnostically active radionuclide” is a radionuclide, which is suitable for or useful in at least the diagnosis of a disease. It will, however, also be acknowledged by a person skilled in the art that the use of said diagnostically active radionuclide may not be limited to diagnostic purposes, but can encompass their use in therapy and theragnostics.

In an embodiment, and as preferably used herein, a “therapeutically active compound” is a compound, which is suitable for or useful in at least the treatment of a disease.

In an embodiment, and as preferably used herein, a “therapeutic agent” or a “therapeutically active agent” is a compound which is suitable for or useful in at least the treatment of a disease. In an embodiment, and as preferably used herein, a “therapeutically active radionuclide” is a radionuclide which is suitable for or useful in at least the treatment of a disease. It will, however, also be acknowledged by a person skilled in the art that the use of said therapeutically active radionuclide may not be limited to therapeutically purposes, but can encompass their use in diagnosis and theragno sties.

In an embodiment, and as preferably used herein, a “theragnostically active compound” is a compound, which is suitable for or useful in both the diagnosis and therapy of a disease.

In an embodiment, and as preferably used herein, a “theragnostic agent” or a “theragnostically active agent” is a compound which is suitable for or useful in both the diagnosis and therapy of a disease.

In an embodiment, and as preferably used herein, a “theragnostically active radionuclide” is a radionuclide, which is suitable for or useful in both the diagnosis and therapy of a disease.

In an embodiment, and as preferably used herein, “theragnostics” is a method for the combined diagnosis and therapy of a disease. In certain embodiments, the combined diagnostically and therapeutically active compounds used in theragnostics are radiolabeled.

In an embodiment, and as preferably used herein, “treatment of a disease” is treatment and/or prevention of a disease.

In an embodiment, and as preferably used herein, the terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition; or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

In an embodiment, and as preferably used herein, “preventing” or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.

In an embodiment, and as preferably used herein, the term “subject” or “patient” includes a mammal. The mammal can be, e.g., any mammal, e.g., a human, companion animal, pet, livestock, dog, cat, horse, and cow. In an embodiment, and as preferably used herein, a “disease involving the prostate specific membrane antigen (PSMA) protein” is a disease involving cells showing upregulated expression of PSMA, which are a or the cause for the disease and/or the symptoms of the disease, or are part of the pathology underlying the disease.

In an embodiment, and as preferably used herein, a "target cell” or “target tissue” is a cell or tissue, which is expressing prostate specific membrane antigen (PSMA) and is a or the cause for a disease and/or the symptoms of a disease, or is part of the pathology underlying a disease.

In an embodiment, and as preferably used herein, a “non-target cell” or “non-target tissue” is a cell or tissue, which is either not expressing prostate specific membrane antigen (PSMA) and/or is not a or the cause for a disease and/or the symptoms of a disease, or is part of the pathology underlying a disease.

In an embodiment, and as preferably used herein, a “neoplasm” is an abnormal new growth of cells. The cells in a neoplasm grow more rapidly than normal cells and will continue to grow if not treated. A neoplasm may be benign or malignant.

In an embodiment, and as preferably used herein, a “tumor” is a mass lesion that may be benign or malignant.

In an embodiment, and as preferably used herein, a “cancer” is a malignant neoplasm.

In an embodiment, and as preferably used herein, a “pharmaceutically acceptable excipient” refers to an ingredient other than the active agent(s) and/or compound(s) that is suitable for use in a pharmaceutical composition, including, but not limited to, pharmaceutically acceptable adjuvants, diluents, carriers, buffers, binders, colorants, lubricants, fillers, disintegrants, preservatives, surfactants, and stabilizers.

In an embodiment, and as preferably used herein, a “linkage” is an attachment of two atoms of two independent moieties. A preferred linkage is a chemical bond or a plurality of chemical bonds. Preferably a chemical bond is a covalent bond or a plurality of chemical bonds. Preferably the linkage is a covalent bond or a coordinate bond. As preferably used herein, an embodiment of a coordinate bond is a bond or group of bonds as realized when a metal is bound by a chelator. Depending on the type of atoms linked and their atomic environment different types of linkages are created. These types of linkage are defined by the type of atom arrangements created by the linkage. For instance, the linking of a moiety comprising an amine with a moiety comprising a carboxylic acid leads to a linkage named amide (which is also referred to as amide linkage, -CO-N-, -N-CO-). It will be acknowledged by a person skilled in the art that this and the following examples of creating linkages are only prototypical examples and are by no means limiting the scope of the instant application. It will be acknowledged by a person in the art that the linking of a moiety comprising an isothiocyanate with a moiety comprising an amine leads to thiourea (which is also referred to as a thiourea linkage, -N-CS-N-), and linking of a moiety comprising a C atom with a moiety comprising a thiol-group (-C-SH) leads to thioether (which is also referred to as a thioether linkage, -C-S- C). A non-limiting list of examples of linkages used in connection with the chelator and linker of the disclosure and their characteristic type of atom arrangement is presented Table 1.

Table 1: Examples of reactive groups which, in some embodiments of the disclosure, are used in the formation of linkages between the chelator and linker or directly between the chelator and the moiety Y of a compound of Formula 3 the disclosure are summarized in Table 2. It will, however, be understood by a person skilled in the art that neither the linkages nor the reactive groups forming such linkages for the formation of the compounds of the disclosure are limited to the ones of Table 2.

Table 2:

In an embodiment, and as preferably used herein, the term “activated carboxylic acid” refers to a carboxylic acid group with the general formula -CO-X, wherein X is a leaving group. For example, activated forms of a carboxylic acid group may include, but are not limited to, acyl chlorides, symmetrical or unsymmetrical anhydrides, and esters. In some embodiments, the activated carboxylic acid group is an ester with pentafluorophenol, nitrophenol, benzotriazole, azabenzotriazole, thiophenol or N-hydroxysuccinimide (NHS) as leaving group.

In an embodiment, and as preferably used herein, the term “mediating a linkage” means that a linkage or a type of linkage is established, preferably a linkage between two moieties.

Compounds of the disclosure may contain amino acids, for example, as the moiety L and/or as the moiety Y of L- Y as provided in Formula 3 herein. Conventional amino acids, also referred to as natural amino acids are identified according to their standard three-letter codes and one- letter abbreviations, as set forth in Table 3.

Table 3: Conventional amino acids and their abbreviations Non-conventional amino acids, also referred to as non-natural amino acids, are any kind of non-oligomeric compound which comprises an amino group and a carboxylic group and is not a conventional amino acid.

For amino acids, in their abbreviations the first letter indicates the stereochemistry of the C-a- atom if applicable. For example, a capital first letter indicates that the L-form of the amino acid is present in the peptide sequence, while a lower case first letter indicating that the D-form of the correspondent amino acid is present in the peptide sequence.

In an embodiment, and as preferably used herein, an aromatic amino acid is any kind of amino acid which comprises an aryl or heteroaryl group.

In an embodiment, and as preferably used herein, an aromatic a-amino acid is any kind of a- amino acid which comprises an aryl or heteroaryl group.

In an embodiment, and as preferably used herein, an a-amino acid is an amino acid wherein the amino and the carboxyl group are substituents of the same carbon atom.

Those skilled in the art will recognize if a stereocenter exists in the compounds disclosed herein irrespective thereof whether such stereocenter is part of an amino acid moiety or any other part or moiety of the compound of the disclosure. Accordingly, the present disclosure includes possible stereoisomers and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

In the present disclosure, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like. In an embodiment, and as preferably used herein, the term “effector domain” refers to a chelator complexed with a therapeutically active nuclide, a chelator complexed with a diagnostically active nuclide, a chelator, or an effector.

In an embodiment, and as preferably used herein, an “effector” refers to an active agent that inhibits or prevents a cellular function and/or causes cell death or destruction. Effectors include, but are not limited to the following active agents: theragnostically active agents, diagnostically active agents, therapeutically active agents, theragnostically active nuclides, diagnostically active nuclides, therapeutically active nuclides, theragnostically active radionuclides, diagnostically active radionuclide, therapeutically active radionuclide, radioactive isotopes, chemotherapeutic agents or drugs, growth inhibitory agents, enzymes and fragments thereof such as nucleolytic enzymes, antibiotics, toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof, and the various antitumor or anticancer agents disclosed below.

The compounds of the present disclosure may comprise a linker. In certain embodiments, the linker can be moiety L. In certain embodiments, the linker can be moiety L-Y. In an embodiment, and as preferably used herein, a linker is an element, moiety, or structure, which separates two parts of a molecule. In the present disclosure, the linker forms covalent bonds with both the effector domain and the respective part of the compounds of the disclosure, where the linker is attached to the PSMA binding domain (Formula 2). The linker may, in principle, be any chemical group, which is capable of forming bonds with both the effector domain and the PSMA binding domain of the compounds of the disclosure at the specified positions.

An important property or feature of a linker as used herein is that it spaces apart the effector domain and the PSMA binding domain of the compounds of the disclosure. This may be especially important in cases where the target binding ability of the PSMA binding domain is affected by the close proximity of the effector, or more specifically the chelator. However, the overall linker length in its most extended conformer should not exceed 1000 A, for example, not more than 900 A, not more than 800 A, not more than 700 A, not more than 600 o o o o o

A, not more than 500 A, not more than 200 A, not more than 150 A, or not more than 100 A. In some embodiments, the linker has 1 to 100 atoms, or 1 to 60 atoms, or 1 to 30 atoms, or 1 to 15 atoms, or 1 to 10 atoms, or 1 to 5, or 2 to 20 atoms in length. In some embodiments, the linker has 1 to 10 atoms in length.

In some embodiments, a linker can comprise one or more amino acid residues. In some embodiments, the linker comprises 1 to 20, or 1 to 3, or 1 to 5, or 1 to 10, or 5 to 10, or 5 to 20 amino acid residues. In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues. In some embodiments, the linker comprises 1 to 5 amino acid residues. In some embodiments, one or more amino acids of the linker are unnatural amino acids.

The linker can comprise flexible and/or rigid regions. Exemplary flexible linker regions include those comprising Gly and Ser residues (“GS” linker), glycine residues, alkylene chain, PEG chain, etc. Exemplary rigid linker regions include those comprising alpha helix-forming sequences (e.g., EAAAK), proline -rich sequences, and regions rich in double and/or triple bonds.

The linker can be cleavable, e.g., under physiological conditions, e.g., under intracellular conditions, such that cleavage of the linker releases the chelator and radionuclide in the intracellular environment. The linker can be, e.g., a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. In some embodiments, the peptidyl linker is at least two amino acids long or at least three amino acids long. Cleaving agents can include, for example, cathepsins B and D and plasmin. In other embodiments, the linker is not cleavable. In some embodiments, the linker is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values. For example, the pH-sensitive linker can be hydrolyzable under acidic conditions. For example, a linker can be an acid-labile linker that is hydrolyzable in the lysosome (e.g., a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like). Such linkers can be relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome. In some embodiments, the hydrolyzable linker is a thioether linker.

In some embodiments, the linker is L-Y, where L mediates the linkage of the effector domain to Y.

In some embodiments, L is an individual building block which is connected independently to its neighbors by a linkage selected from the group comprising an amide linkage, a urea linkage, a carbamate linkage, an ether linkage, a thioether linkage and a sulfonamide linkage.

In some embodiments, L is an amino acid. In some embodiments, L is an amino acid, wherein the amino and carboxyl group of the amino acid are spaced at least two atoms apart and those amino acids may be, as non-limiting examples, selected from the group comprising P-amino acids, y-amino acids, 6-amino acids, s-amino acids and co-amino acids. In some embodiments, L is an amino acid, wherein the amino acid is a cyclic amino acid or a linear amino acid. It will be appreciated by a person skilled in the art that in the case of an amino acid with stereogenic centers all stereoisomeric forms may occur in the linker.

In some embodiments, L is an amino acid, wherein the amino acid is selected from a group comprising amino acids which are represented by generic structures (A), (B), (C), and (D):

It is within the present disclosure that such amino acid is not further substituted. It is, however, also within the present disclosure that such amino acid is further substituted, including where the substitution is CO-NH2 and/or Ac-NH- substitution.

Representative examples of amino acids according to generic structure (A) are comprising B- alanine (Bal), y-aminobutyric acid (GABA), aminopentanoic acid, aminohexanoic acid and homologs with up to 10 CH2 groups.

Representative examples of amino acids according to generic structure (C) and generic structure (D), which are optionally used as L, are 3 -aminomethyl-benzoic acid, 4-aminomethyl- benzoic acid, anthranilic acid, 3-amino benzoic acid and 4-amino benzoic acid.

In a further embodiment, L is an amino acid which contains, for example as a backbone, an oligo- or polyether fragment. In some embodiments, such polyether is polyethylene glycol and consists of up to 30 monomer units. In some embodiments, an amino acid comprising such polyether shows an increase in hydrophilicity compared to an amino acid not comprising such poly ether. If incorporated into L, the result is typically an increase in hydrophilicity. An embodiment of this kind of amino acid is depicted in general structure (E), wherein it will be acknowledged that such amino acid may comprise 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ethylene oxide moieties:

In some embodiments, ethylene glycol containing amino acids are Ttds (N-(3-{2-[2-(3-Amino- propoxy)-ethoxy] -ethoxy }-propyl)-succinamic acid, structure (F)) and O2Oc ([2-(2- Aminoethoxy )-ethoxy] -acetic acid, structure (G)), which are as follows:

(F) (G)

In some embodiments, L comprises a carbocycle or a heterocycle.

In a further embodiment the amino and carboxyl group of the amino acid are spaced at least four atoms apart.

In some embodiments, L is selected from the group consisting of Formula 9, 10, 11, 12, and 13

Formula 9 Formula 10 Formula 11 Formula 12 Formula 13.

In addition to bioactivity effects the choice of the linker structure opens the chance to tune important physicochemical properties of the molecule by introduction of polarity or multiple charges.

In an embodiment, Y is an aromatic amino acid. In some embodiments, Y is an aromatic a- amino acid which includes the D- as well as L-configuration and, for a person skilled in the art, it is clear that the side chain may comprise mono-, bi- or oligo cyclic ring systems which can be also of heterocyclic nature and wherein the amino group of Y is covalently bound to L and the carboxyl carbon atom of Y is covalently bound to the nitrogen as shown in Formula 3.

In some embodiments, Y is a structure selected from the group consisting of Formula 4, 5, 6, 7, and 8

Formula 4 Formula 5 Formula 6 Formula 7 Formula 8 .

In an embodiment, the compound of the disclosure comprises a chelator. In some embodiments, the chelator is part of the compound of the disclosure, whereby the chelator is either directly or indirectly such as by a linker attached to the compound of the disclosure. In some embodiments, the chelator is a chelator which forms metal chelates, for example, comprising at least one radioactive metal. The at least one radioactive metal is, for example, useful in or suitable for diagnostic and/or therapeutic and/or theragnostic use and is, for example, useful in or suitable for imaging and/or radiotherapy.

Chelators in principle useful in and/or suitable for the practicing of the instant disclosure, including diagnosis and/or therapy of a disease, are known to the person skilled in the art. A wide variety of respective chelators is available and has been reviewed, e.g., by Banerjee et al. (Banerjee, et al., Dalton Trans, 2005, 24: 3886), and references therein (Price, et al., Chem Soc Rev, 2014, 43: 260; Wadas, et al., Chem Rev, 2010, 110: 2858). Such chelators include, but are not limited to linear, cyclic, macrocyclic, tetrapyridine, N3S, N2S2 and N4 chelators as disclosed in US 5,367,080 A; US 5,364,613 A; US, 5,021,556 A; US 5,075,099 A; and US 5,886,142 A.

In some embodiments, the metal chelator is capable of binding a radioactive nuclide. The binding can be direct, e.g., the metal chelator can make ionic, covalent, dipolar, or ion-dipole interactions with the radioactive atom. The binding can also be indirect, e.g., the metal chelator binds to a molecule that comprises a radioactive atom. In some embodiments, the metal chelator comprises, or is, a macrocycle. In some embodiments, the metal chelator comprises, or is, DOTA or NOTA. In some embodiments, the metal chelator comprises a macrocycle, e.g., a macrocycle comprising an O and/or a N, DOTA, NOTA, one or more amines, one or more ethers, one or more carboxylic acids, EDTA, DTPA, TETA, DO3A, PCTA, or desferrioxamine.

In some embodiments, the metal chelator comprises a plurality of amines. In some embodiments, the metal chelator includes 4 or more N, 4 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator does not comprise S. In some embodiments, the metal chelator comprises a ring. In some embodiments, the ring comprises an O and/or an N. In some embodiments, the metal chelator is a ring that includes 3 or more N, 3 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator is polydentate.

Representative chelating agents and their derivatives include, but are not limited to AAZTA, BAT, CDTA, DTA, CyEDTA, EDTMP, DTPMP, DTPA, CyDTPA, Cy2DTPA, DTPA-MA, DTPA-BA, BOPA, NTA, NOC, NOTP, CY-DTA, DTCBP, CTA, cyclam, CB-Cyclam, cyclen, TETA, sarcophagine, CPTA, TEAMA, Cyclen, DO3A, DO2A, TRITA, DATA, DFO, DATA(M), DATA(P), DATA(Ph), DATA(PPh), DEDPA, H ₄ octapa, H ₂ dedpa, Hsdecapa, H ₂ azapa, H2CHX-DEDPA, DFO-Chx-MAL, DFO-p-SCN, DFO- 1 AC, DFO-BAC, p-SCN- Bn-DFO, DFO-pPhe-NCS, DFO-HOPO, DFC, diphosphine, DOTA, DOTAGA, DOTA- MFCO, DOTAM, DOT AM-mono-acid, DOTA-MA, DOTA-pNB, DOTA-4AMP, nitro- DOTA, nitro-PA-DOTA, p-NCS-Bz-DOTA, PA-DOTA, DOTA-NCS, DOTA-NHS, CB- DO2A, PCTA, p-NH ₂ -Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-DOTA, DOTMA, NB- DOTA, H4NB-DOTA, H4TCE-DOTA, HOPO, 3,4,3-(Li-l,2-HOPO), TREN(Me-3,2- HOPO), TCE-DOTA, DOTP, DOTMP, DOTEP, DOTMPE, F-DOTPME, DOTPP, DOTBzP, DOTA-monoamide, DOXP, p-NCS-DOTA, p-NCS-PADOTA, p-NCS-TRITA, TRITA, TETA, 3p-C-DEPA, 3p-C-DEPA-NCS, p-NH2-BN-OXO-DO3A, p-SCN-BN-TCMC, TCMC, 4-aminobutyl-DOTA, azido-mono-amide-DOTA, BCN-DOTA, butyne-DOTA, BCN- DOTA-GA, DOA3P, DO2a2p, DO2A(trans-H2do2a), DO3A, DO3A-thiol, DO3AtBu-N-(2- aminoethyl)ethanamide, DO3TMP-monoamide, DO2AP, CB-DO2A, C3B-DO2A, HP-DO3A, DOTA-NHS-ester, maleimide-DOTA-GA, maleimido-mono-aminde-DOTA, maleimide- DOTA, NH2-DOTA-GA, NH2-PEG4-DOTA-GA, GA, p-NFE-Bn-DOTA, p-NO2-Bn- DOTA, p-SCN-Bn-DOTA, p-SCN-Bz-DOTA, TA-DOTA, TA-DOTA-GA, OTTA, DOXP, TSC, FSC, DTC, DTCBP, PTSM, ATSM, H2ATSM, H2PTSM, Dp44mT, DpC, Bp44mT, QT, hybrid thiosemicarbazone-benzothiazole, thiosemicarbazone-styrylpyridine tetradentate ligands H ₂ L2-4, HBED, HBED-CC, dmHBED, dmEHPG, HBED-nn, SHBED, Br-Me2HBED, BPCA, HEHA, BF-HEHA, deferiprone, THP, HYNIC (2-hydrazino nicotinamide), NHS- HYNIC, HYNIC-Kp-DPPB, HYNIC-Ko-DPPB, (HYNIC)(tricine)2, (HYNIC)(EDDA)C1, p- EDDHA, AIM, AIM A,IAM B, MAMA, MAMA-DGal, MAMA-MGal, MAMA-DA, MAMA-HAD, PSC, macropa, macropaquin, macroquin- S 03, Crown, N _X S _4-X , N2S2, N3S, N4, MAG3B, NOTA, NODAGA, SCN-Bz-NOTA-R, NOT-P (NOTMP), NOT AM, p-NCS- NOTA, TACN, TACN-TM, NETA, NETA-monoamine, p-SCN-PhPr-NE3TA, C-NE3TA- NCS, C-NETA-NCS, 3p-C-NETA, NODASA, NOPO, NODA, NODA-MPAA, NO2A, N- benzyl-NODA, C-NOTA, BCNOT-monoamine, maleimido-mono-amide-NOTA, NO2A- azide, N02A-butyne, NO2AP, NO3AP, N-NOTA, oxo-DO3A, p-NH2-Bn-NOTA, p-NFE-Bn- oxo-DO3A, p-N02-Bn-cyclen, p-SCN-Bn-NOTA, p-SCN-Bn-oxo-DO3A, TRAP, PEPA, BF- PEPA, pycup, pycup2A, pycuplAIBn, pycup2Bn, SarAr-R, DiAmSar, AmBaSar-R, siamSar, Sar, Tachpyr, tachpyr-(6-Me), TAM A, TAM B, TAME, TAME-Hex, THP-Ph-NCS, THP- NCS, THP-TATE, NTP, H3THP, THPN, CB-TE2A, PCB-TE1A1P,_TETA-NHS, CPTA, CPTA-NHS, CB-TE1K1P, CB-TE2A, TE2A, H2CB-TE2A, TE2P, CB-TE2P, MM-TE2A, DM-TE2A, 2C-TETA, 6C-TETA, BAT, BAT-6, NHS-BAT ester, SSBAT, CHX-A”-DTPA, SCN-CHX-A-DTPA-P, SCN-TETA, TMT-amine, p-BZ-HTCPP, H ₄ pypa, H ₄ octox, p-N02- Bn-neunpa, p-SCN-Bn-H ₄ neunpa, TTHA, tBu4pypa-C7-NHS, H ₄ neunpa, H2macropa, BT- DO3A, DO3A-Nprop, DO3AP, DOTPMB, DOTAMAE, DOTAMAP, DO3AMBu, DEPA, p- NO2-Bn-PCTA, symPC2APA, symPCA2PA, asymPC2APA, asymPCA2PA, ^99m Tc(CO) ₃ - Chelators, and MeO-DOTA-NCS.

HYNIC, DTPA, EDTA, DOTA, TETA, bisamino bisthiol (BAT)-based chelators as disclosed in US 5,720,934; desferrioxamine (DFO) as disclosed in Doulias et al. (Doulias, et al., Free Radic Biol Med, 2003, 35: 719), tetrapyridine and N3S, N2S2 and N ₄ chelators as disclosed in US 5,367,080 A; US 5,364,613 A; US 5,021,556 A; US 5,075,099 A; and US 5,886,142 A, whereby all of the references are included herein by reference in their entirety. 6-amino-6- methylperhydro-l,4-diazepine-/V,/\/',/\/'',/\/''-tetraacetic acid (AAZTA) is disclosed in Pfister et al. (Pfister, et al., EJNMMI Res, 2015, 5: 74), deferiprone, a l,2-dimethyl-3,4- hydroxypyridinone and hexadentate tris(3,4-hydroxypyridinone) (THP) are disclosed in Cusnir et al. (Cusnir, et al., Int J Mol Sci, 2017, 18), monoamine-monoamide dithiol (MAMA)-based chelators are disclosed in Demoin et al. (Demoin, et al., Nucl Med Biol, 2016, 43: 802), macropa and analogues are disclosed in Thiele et al. (Thiele, et al., Angew Chem Int Ed Engl, 2017, 56: 14712), 1,4,7, 10, 13,16-hexaazacyclohexadecane-N,N',N",N"',N"",N - hexaacetic acid (HEHA) and PEPA analogues are disclosed in Price and Orvig (Price, et al., Chem Soc Rev, 2014, 43: 260), pycup and analogous are disclosed in Boros et al. (Boros, et al., Mol Pharm, 2014, 11: 617), N, N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED), 1,4,7, 10-tetrakis (carbamoylmethyl)-l,4,7,10-tetraazacyclododecane (TCM), 2- [(carboxymethyl)]-[5-(4-nitrophenyl- 1 - [4,7 , lO-tris-(carboxymethyl)- 1,4,7, 10- tetraazacyclododecan-l-yl]pentan-2-yl)-amino] acetic acid (3p-C-DEPA), CB-TE2A, TE2A, TE1A1P, DiAmSar, l-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-ei cosane- 1,8-diamine (SarAr), NETA, , tris(2-mercaptoethyl)-l,4,7-triazacyclononane (TACN-TM), {4-[2-(bis-carboxymethyl-amino)-ethyl]-7-carboxymethyl-[l,4, 7]triazonan-l-yl}-acetic acid (NETA), diethylenetriaminepentaacetic acid (DTP), 3-({4,7-bis-[(2-carboxy-ethyl)-hydroxy- pho sphinoy Imethy 1] -[1,4,7] triazonan- 1 -y Imethy 1 } -hy droxy-pho sphinoy 1) -propionic acid

(TRAP), NOPO, H4octapa, SHBED, BPCA, 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca- 1(15), 11, 13 -triene- 3, 6, 9, -triacetic acid (PCTA), and 1,4,7,10,13-pentaazacyclopentadecane- N,N',N",N"',N""-pentaacetic acid (PEPA) are disclosed in Price and Orvig (Price, et al., Chem Soc Rev, 2014, 43: 260), l-hydroxy-2-pyridone ligand (HOPO) is disclosed in Allott et al. (Allott, et al., Chem Commun (Camb), 2017, 53: 8529), [4-carboxymethyl-6- (carboxymethyl-methyl-amino)-6-methyl-[l,4]diazepan-l-yl]-ac etic acid (DATA) is disclosed in Tomesello et al. (Tomesello, et al., Molecules, 2017, 22: 1282), tetrakis(aminomethyl)methane (TAM) and analogues are disclosed in McAuley 1988 (McAuley, et al., Canadian Journal of Chemistry, 1989, 67: 1657), hexadentate tris(3,4- hydroxypyridinone) (THP) and analogues are disclosed in Ma et al. (Ma, et al., Dalton Trans, 2015, 44: 4884).

The diagnostic and/or therapeutic use of some of the above chelators is described in the prior art. For example, 2-hydrazino nicotinamide (HYNIC) has been widely used in the presence of a coligand for incorporation of ^99m Tc and ¹⁸⁶ ’ ¹⁸⁸ R _e (Schwartz, et al., Bioconjug Chem, 1991, 2: 333; Babich, et al., J Nucl Med, 1993, 34: 1964; Babich, et al., Nucl Med Biol, 1995, 22: 25); DTPA is used in Octreoscan® for complexing ^{i n} In and several modifications are described in the literature (Li, et al. , Nucl Med Biol, 2001, 28: 145; Brechbiel, et al. , Bioconjug Chem, 1991, 2: 187); DOTA-type chelators for radiotherapy applications are described by Tweedie et al. (US Pat 4,885,363); other polyaza macrocycles for chelating trivalent isotopes metals are described by Eisenwiener et al. (Eisenwiener, et al., Bioconjug Chem, 2002, 13: 530); and N4- chelators such as a ^99m Tc-N4-chelator have been used for peptide labeling in the case of minigastrin for targeting CCK-2 receptors (Nock, et al., J Nucl Med, 2005, 46: 1727).

In an embodiment, the metal chelator is selected from the group including, but not limited to, DOTA, DOTAGA, NOPO, PCTA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB- TE2A, DTPA, CHX-A“-DTPA, DFO, Macropa, Crown, DOT AM (also called TCMC), PSC, HOPO, HEHA, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, NxS4-x (N4, N2S2, N3S), Hynic, ^99m Tc(CO)3-chelators, and their analogs, more preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, PSC, Macropa, Crown, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, more preferably DOTA, DOTAGA, NOPO, PCTA, DOTAM, PSC, Macropa, Crown, NOTA, and NODAGA; and most preferably DOTA, NOPO, PCTA, Macropa and Crown, wherein

DOTA stands for 1,4,7, 10-tetrazacyclododecane- 1,4,7, 10-tetraacetic acid,

DOTAGA stand for 1,4, 7, 10-tetraazacyclodocecane,l -(glutaric acid)-4,7,10-triacetic acid,

DOTAM (also called TCMC) stands for l,4,7,10-tetrakis[carbamoylmethyl]-l,4,7,10- tetracyclodecane,

DOTP stands for 1,4,7, 10-tetraazacyclododecane- 1,4,7, 10-tetra(methylene phosphonic acid),

NOTA stands for 1,4, 7 -triazacyclononanetriacetic acid,

NODAGA stands for 1,4,7-triazacyclononane-N-glutaric acid-N',N"-diacetic acid,

NODA-MPAA stands for 1, 4, 7 -triazacyclononane- 1,4-diacetate-methyl phenylacetic acid,

NOPO stands for 3-{ [4,7-Bis-(hydroxy-hydroxymethyl-phosphinoylmethyl)- [ 1 ,4,7]triazonan- 1 -ylmethyl] -hydroxy -pho sphinoyl } -propionic acid

PCTA stands for 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-l(15),l l,13-triene-3,6,9,- triacetic acid,

HBED stands for bis(2-hydroxybenzyl) ethylenediaminediacetic acid, TETA stands for l,4,8,l l-tetraazacyclododecane-l,4,8,l l-tetraacetic acid,

CB-TE2A stands for 4,1 l-bis-(carboxymethyl)-l, 4,8,11 -tetraazabicyclo [6.6.2]- hexadecane,

DTPA stands for diethylenetriaminepentaacetic acid,

CHX-A”-DTPA stands for [(2-{ [2-(bis-carboxymethyl-amino)-cyclohexyl]- carboxymethyl-amino } -ethyl)-carboxymethyl-amino] -acetic acid,

DFO stands for the desferal or desferrioxamine type group of chelators, the chemical name of the non-limiting example is N-[5-({3-[5-(acetyl-hydroxy-amino)-pentylcarbamoyl]- propionyl]-hydroxy-amino)-pentyl]-N'-(5-amino-pentyl)-N'-hyd roxy-succinamide,

Macropa stands for N,N’-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown,

Crown stands for (7,13,16-tris-carboxymethyl-l,10-dioxa-4,7,13,16-tetraaza- cyclooctadec-4-yl)-acetic acid,

PSC stands for (7-carbamoylmethyl-4,10-bis-carboxymethyl-l,4,7,10tetraaza-c yclododec- l-yl)-acetic acid,

HOPO stands for the octadentate hydroxypyridinone-type group of chelators, the structure of a non-limiting example is shown below,

HEHA stands for l,4,7,10,13,16-hexaazacyclooctadecane-N,N',N'',N"',N"",N""'- hexaacetic acid,

TRAP stands for 3-({4,7-bis-[(2-carboxy-ethyl)-hydroxy-phosphinoylmethyl]- [ 1 ,4,7]triazonan- 1 -ylmethyl] -hydroxy -pho sphinoyl) -propionic acid,

THP stands for hexadentate tris(3,4-hydroxypyridinone),

DATA stands for [4-carboxymethyl-6-(carboxymethyl-methyl-amino)-6-methyl- [l,4]diazepan-l-yl]-acetic acid,

NOTP stands for 1 ,4,7-triazacyclononanc-N,N'N''-tris(mcthylcnc phosphonic) acid),

Sarcophagine stands for 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane, FSC stands for 3,15,27-triamino-7,19,31-trihydroxy-10,22,34-trimethyl-l,13, 25-trioxa- 7,19,31-triaza-cyclohexatriaconta-9,21,33-triene-2,8,14,20,2 6,32-hexaone,

NETA stands for {4-[2-(bis-carboxymethyl-amino)-ethyl]-7-carboxymethyl-

[1,4,7] triazonan- 1 -y 1 } - acetic acid,

H4octapa stands for AA ^f '-(6-carboxy-2-pyridylmcthyl)-AA ^f '-diacctic acid- 1,2- diaminoethane,

Pycup stands for l,8-(2,6-Pyridinedimethylene)-l,4,8,l l-tetraazacyclo-tetradecane,

HYNIC stands for 6-hydrazino-nicotinic acid,

N _X S4-X (N4, N2S2, N3S) stands for a group of tetradentate chelators with N-atoms (basic amine or non-basic amide) and thiols as donors stabilizing Tc-complexes, especially Tc(V)- oxo complexes. The structure of one representative non-limiting example N4 is shown below, and N4 stands for N,N'-bis-(2-amino-ethyl)-propane-l,3-diamine,

" ^m Tc(CO)3-chelators stands for bi- or tridendate chelators capable of forming stable complexes with technetium tricarbonyl fragments.

It will be acknowledged by someone skilled in the art, that in certain embodiments the chelators additionally comprise one or more functional groups or functionalities allowing attachment to the compounds of the invention.

The chemical structures of said chelators being as follows: pycup CB-TE2A Sarcophagine

It will be acknowledged by a person skilled in the art that the chelator, in principle, may be used regardless of whether the compound of the disclosure is used in or suitable for diagnosis or therapy. Such principle is, among others, outlined in international patent application WO 2009/109332 Al.

It will be further acknowledged by a person skilled in the art that the presence of a chelator in the compound of the disclosure includes, if not stated otherwise, the possibility that the chelator is complexed to any metal complex partner, i.e., any metal which, in principle, can be complexed by the chelator. An explicitly mentioned chelator of a compound of the disclosure or the general term chelator in connection with the compound of the disclosure refers either to the uncomplexed chelator as such or to the chelator to which any metal complex partner is bound, wherein the metal complex partner is any radioactive or non-radioactive metal complex partner. In some embodiments, the chelator metal complex, i.e. the chelator to which the metal complex partner is bound, is a stable chelator metal complex.

Non-radioactive chelator metal complexes have several applications, e.g., for assessing properties like stability or activity which are otherwise difficult to determine. One aspect is that cold variants of the radioactive versions of the metal complex partner (e.g., non-radioactive Gallium, Lutetium or Indium complexes as described in the examples) can act as surrogates of the radioactive compounds. Furthermore, they are valuable tools for identifying metabolites in vitro or in vivo, as well as for assessing toxicity properties of the compounds of disclosure. Additionally, chelator metal complexes can be used in binding assays utilizing the fluorescence properties of some metal complexes with distinct ligands (e.g., Europium salts).

Chelators can be synthesized or are commercially available with a wide variety of (possibly already activated) groups for the conjugation to peptides or amino acids. Direct conjugation of a chelator to an amino-nitrogen of the respective compound of disclosure is possible for chelators selected from the group consisting of DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, DTPA, CHX-A”-DTPA, macropa, HBED, CB-TE2A, DFO, THP and N4, for example DOTA, DOTAGA, NODAGA and macropa. For example, the linkage in this respect is an amide linkage.

Direct conjugation of an isothiocyanate-functionalized chelator to an amino-nitrogen of the respective compound of disclosure is possible for chelators selected from the group consisting of DOTA, DOTAGA, NOTA, NODAGA, DTPA, CHX-A”-DTPA, DFO, and THP, for example, DOTA, DOTAGA, NOTA, NODAGA, DTPA, and CHX-A”-DTPA. The preferred linkage in this respect is a thiourea linkage.

Functional groups at a chelator which are ideal precursors for the direct conjugation of a chelator to an amino-nitrogen are known to a person skilled in the art and include, but are not limited to, carboxylic acid, activated carboxylic acid, e.g., active ester like for instance NHS- ester, pentafluorophenol-ester, HOBt-ester and HOAt-ester, isothiocyanate.

It will be acknowledged by a person skilled in the art that the radioactive nuclide which is or which is to be attached to the compound of the disclosure, is selected taking into consideration the disease to be treated and/or the disease to be diagnosed, respectively, and/or the particularities of the patient and patient group, respectively, to be treated and to be diagnosed, respectively.

In the present disclosure, a radioactive nuclide is also referred to as radionuclide. Radioactive decay is the process by which an atomic nucleus of an unstable atom loses energy by emitting ionizing particles (ionizing radiation). There are different types of radioactive decay. A decay, or loss of energy, results when an atom with one type of nucleus, called the parent radionuclide, transforms to an atom with a nucleus in a different state, or to a different nucleus containing different numbers of protons and neutrons. Either of these products is named the daughter nuclide. In some decays the parent and daughter are different chemical elements, and thus the decay process results in nuclear transmutation (creation of an atom of a new element). For example, the radioactive decay can be alpha decay, beta decay, and gamma decay. Alpha decay occurs when the nucleus ejects an alpha particle (helium nucleus). This is the most common process of emitting nucleons, but in rarer types of decays, nuclei can eject protons, or specific nuclei of other elements (in the process called cluster decay). Beta decay occurs when the nucleus emits an electron (P’-decay) or positron (P ⁺ -decay) and a type of neutrino, in a process that changes a proton to a neutron or the other way around. By contrast, there exist radioactive decay processes that do not result in transmutation. The energy of an excited nucleus may be emitted as a gamma ray in gamma decay, or used to eject an orbital electron by interaction with the excited nucleus in a process called internal conversion, or used to absorb an inner atomic electron from the electron shell whereby the change of a nuclear proton to neutron causes the emission of an electron neutrino in a process called electron capture (EC), or may be emitted without changing its number of proton and neutrons in a process called isomeric transition (IT). Another form of radioactive decay, the spontaneous fission (SF), is found only in very heavy chemical elements resulting in a spontaneous breakdown into smaller nuclei and a few isolated nuclear particles.

In an embodiment, described herein are compounds that comprise a radionuclide. Generally, the type of radionuclide used in a therapeutic radiopharmaceutical can be tailored to the specific type of cancer and the type of targeting moiety. Radionuclides that undergo a-decay produce particles composed of two neutrons and two protons, and radionuclides that undergo P-decay emit energetic electrons from their nuclei. Some radionuclides can also emit Auger electrons. In some embodiments, the conjugate comprises an alpha particle-emitting radionuclide. Alpha radiation can cause direct, irreparable double-strand DNA breaks compared with gamma and beta radiation, which can cause single-stranded breaks via indirect DNA damage. The range of these particles in tissue and the half-life of the radionuclide can also be considered in designing the radiopharmaceutical conjugate.

In an embodiment of the present disclosure, the radionuclide can be used for labeling of the compound of the disclosure.

In an embodiment of the present disclosure, the radionuclide is suitable for complexing with a chelator, leading to a radionuclide chelate complex.

In a further embodiment one or more atoms of the compound of the disclosure are of nonnatural isotopic composition, for example these atoms are radionuclides; for example radionuclides of carbon, oxygen, nitrogen, sulfur, phosphorus and halogens. These radioactive atoms are typically part of amino acids, in some case halogen containing amino acids, and/or building blocks and in some cases halogenated building blocks each of the compound of the disclosure.

In one embodiment of the present disclosure, the radionuclide has a half-life that allows for diagnostic and/or therapeutic medical use. Specifically, the half-life is between 1 min and 100 days.

In an embodiment of the present disclosure, the radionuclide has a decay energy that allows for diagnostic and/or therapeutic medical use. Specifically, for y-emitting isotopes, the decay energy is between 0.004 and 10 MeV, for example, between 0.05 and 4 MeV, for diagnostic use. For positron-emitting isotopes, the decay energy is between 0.6 and 13.2 MeV, for example, between 1 and 6 MeV, for diagnostic use. For particle-emitting isotopes, the decay energy is between 0.039 and 10 MeV, for example, between 0.4 and 6.5 MeV, for therapeutic use.

In an embodiment of the present invention, the radionuclide is industrially produced for medical use. Specifically, the radionuclide is available in GMP quality.

In an embodiment of the present disclosure, the daughter nuclide(s) after radioactive decay of the radionuclide are compatible with the diagnostic and/or therapeutic medical use. Furthermore, the daughter nuclides are either stable or further decay in a way that does not interfere with, or may even support, the diagnostic and/or therapeutic medical use. Representative radionuclides, which may be used in connection with the present disclosure are summarized in Table 4. Table 4 includes key properties of relevant radionuclides - half life, decay radiation types, decay energies of transitions with highest probabilities (mean energies for P decays) and absolute intensities (source: https ://www- nds.iaea.org/relnsd/vcharthtml/VChartHTML.html; accessed September 4 ^th , 2020). Table 4: Key properties of relevant radionuclides - half life, decay types and decay energies

12 Mg-28 20.9 h p- 0.156 94.8

Y 0.031 89.0

Y 1.342 54.0

Y 0.942 36.3

Y 0.401 35.9

21 Sc-48 43.7 h p- 0.227 90.0 p- 0.159 10.0

Y 0.984 100.1

Y 1.312 100.1 Y 1.038 97.6

In an embodiment of the present disclosure, the radionuclide is used for diagnosis. In some embodiments, the radioactive isotope is selected from the group including, but not limited to, ⁴³ Sc, ⁴⁴ Sc, ⁵¹ Mn, ⁵² Mn, ⁶⁴ Cu, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁸⁹ Zr, ^94m Tc, " ^m Tc, ^m In, ¹⁵² Tb, ¹⁵⁵ Tb, ¹⁷⁷ Lu, ^2O1 T1, ²⁰³ Pb, ¹⁸ F, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, and ¹²⁵ I. In some embodiments, the radionuclide is selected from ⁴³ Sc, ⁴⁴ Sc, ⁶⁴ Cu, ⁶⁷ Ga, ⁶⁸ Ga, ⁸⁶ Y, ⁸⁹ Zr, " ^m Tc, ⁱⁿ In, ¹⁵² Tb, ¹⁵⁵ Tb, and ²⁰³ Pb. In some embodiments, the radionuclide is selected from ⁶⁴ Cu, ⁶⁸ Ga, and ⁱⁿ In. It will, however, also be acknowledged by a person skilled in the art that the use of said radionuclide is not limited to diagnostic purposes, but encompasses their use in therapy and theragnostics when conjugated to the compound of the disclosure.

In an embodiment of the present disclosure, the radionuclide is used for therapy. In some embodiments, the radioactive isotope is selected from ⁴⁷ Sc, ⁶⁷ Cu, ⁸⁹ Sr, ⁹⁰ Y, ⁱⁿ In, ¹⁵³ Sm, ¹⁴⁹ Tb, ¹⁶¹ Tb, ¹⁷⁷ LU, ¹⁸⁶ Re, ¹⁸⁸ Re, ²¹² Pb, ²¹³ Bi, ²²³ Ra, ²²⁴ Ra ²²⁵ Ac, ²²⁶ Th, ²²⁷ Th, ¹³¹ I, and ²¹¹ At. In some embodiments, the radioactive isotope is selected from ⁴⁷ Sc, ⁶⁷ Cu, ⁹⁰ Y, ¹⁷⁷ Lu, ¹⁸⁸ Re, ²¹² Pb, ²¹³ Bi, ²²⁵ Ac, and ²²⁷ Th. In some embodiments, the radionuclide is selected from ⁹⁰ Y, ¹⁷⁷ Lu, ²¹² Pb, ²²⁵ Ac, and ²²⁷ Th. It will, however, also be acknowledged by a person skilled in the art that the use of said radionuclide is not limited to therapeutic purposes, but encompasses their use in diagnostic and theragnostics when conjugated to the compound of the disclosure.

In an embodiment, the compound of the disclosure is present as a pharmaceutically acceptable salt.

In certain embodiments, a “pharmaceutically acceptable salt” of a compound of the present disclosure is an acid salt or a base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and, for example, without irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues, such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Compounds of the disclosure are capable of forming internal salts, which are also pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts include, but are not limited to, salts of acids, such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2- hydroxyethylsulfonic, nitric, benzoic, 2- acetoxy benzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC-(CH2) _n -COOH where n is any integer from 0 to 4, i.e., 0, 1, 2, 3, or 4, and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein. In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, the use of non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, is preferred.

In certain embodiments, a “pharmaceutically acceptable solvate” of a compound of the disclosure is a solvate of the compound of the disclosure formed by association of one or more solvent molecules to one or more molecules of a compound of the disclosure. In some embodiments, the solvent is one which is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and for example, without irritation, allergic response, or other problem or complication. Such solvent includes an organic solvent, such as alcohols, ethers, esters and amines.

In certain embodiments, a “hydrate” of a compound of the disclosure is formed by association of one or more water molecules to one or more molecules of a compound of the disclosure. Such hydrates include, but are not limited to, a hemi-hydrate, mono-hydrate, dihydrate, trihydrate and tetrahydrate. Independent of the hydrate composition, all hydrates are generally considered as pharmaceutically acceptable.

The compound of the disclosure has a high binding affinity to PSMA and a high inhibitory activity on PSMA. Because of this high binding affinity, the compound of the disclosure is effective as, useful as, and/or suitable as a targeting agent and, if conjugated to another moiety, as a targeting moiety, where the target is PSMA and/or a cell and/or tissue expressing PSMA. In terms of cells and tissues thus targeted by the compound of the disclosure any cell and tissue, respectively, expressing PSMA is or may be targeted.

It is within the present disclosure that the compound of the disclosure is used or is for use in a method for the treatment of a disease as disclosed herein. In certain embodiments, such a method for the treatment of a disease as disclosed herein comprises the step of administering to a subject in need thereof a therapeutically effective amount of the compound of the disclosure. Such a method includes, but is not limited to, curative or adjuvant cancer treatment. It is used as palliative treatment where cure is not possible and the aim is for local disease control or symptomatic relief or as therapeutic treatment where the therapy has survival benefit and it can be curative.

The method for the treatment of a disease as disclosed herein includes the treatment of the diseases disclosed herein, including tumors and cancer, and may be used either as the primary therapy or as second, third, fourth, or last line therapy. It is also within the present disclosure to combine the compound of the disclosure with further therapeutic approaches. It is well known to the person skilled in the art that the precise treatment intent including curative, adjuvant, neoadjuvant, therapeutic, or palliative treatment intent will depend on the tumor type, location, and stage, as well as the general health of the patient.

In an embodiment of the present disclosure, the disease is selected from the group comprising a prostate tumor, a metastasized prostate tumor, a lung tumor, a renal tumor, a glioblastoma, a pancreatic tumor, a bladder tumor, a sarcoma, a melanoma, a breast tumor, a colon tumor, a pheochromocytoma, an esophageal tumor, a stomach tumor, carcinoma, squamous carcinoma (e.g., cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, and gullet), and an adenocarcinoma (e.g., prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, gullet, rectum, uterus, stomach, mammary gland, and ovary), prostate cancer (e.g., metastatic castration resistant prostate cancer), renal cancer (e.g., clear cell carcinoma), head cancer, neck cancer, head and neck cancer, lung cancer (e.g., non-small cell lung cancer), salivary gland cancer, breast cancer, colorectal cancer, esophageal cancer, stomach cancer, liver cancer (e.g., hepatocellular cancer), thyroid cancer, glioblastoma, glioma, gall bladder cancer, laryngeal cancer, leukemia/lymphoma, uterine cancer, skin cancer (e.g., melanoma), endocrine cancer, sarcoma, urinary cancer, pancreatic cancer, gastrointestinal cancer, ovarian cancer, cervical cancer, endometrial cancer, fallopian tube cancer, primary peritoneal cancer, hematological cancer (e.g., diffuse large B cell lymphoma, Hodgkin’s lymphoma, NonHodgkin’s lymphoma, follicular lymphoma, acute myeloid leukemia, or multiple myeloma), cancer of unknown primary, adenomas, and tumor neovasculature.

In some embodiments, the subjects treated with the presently disclosed compounds may be treated in combination with other non-surgical anti-proliferative (e.g., anti-cancer) drug therapy. In some embodiments, the compounds may be administered in combination with an anti-cancer compound such as a cytostatic compound. A cytostatic compound is a compound (e.g., a small molecule, a nucleic acid, or a protein) that suppresses cell growth and/or proliferation. In some embodiments, the cytostatic compound is directed towards the malignant cells of a tumor. In some embodiments, the cytostatic compound is one which inhibits the growth and/or proliferation of vascular smooth muscle cells or fibroblasts.

In some embodiments, the herein-described compounds are used or are for use in combination with a chemotherapeutic agent, e.g., a DNA damaging chemotherapeutic agent. Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors, topoisomerase II inhibitors; alkylating agents; DNA intercalators; DNA intercalators and free radical generators such as bleomycin; and nucleoside mimetics.

In some embodiments, a compound described herein can be administered alone or in combination with one or more additional therapeutic agents. For example, the combination therapy can include a composition comprising a conjugate described herein co-formulated with, and/or coadministered with, one or more additional therapeutic agents, e.g., one or more anti-cancer agents, e.g., cytotoxic or cytostatic agents, immune checkpoint inhibitors, hormone treatment, vaccines, and/or immunotherapies. In some embodiments, the conjugate is administered in combination with other therapeutic treatment modalities, including surgery, cryosurgery, and/or chemotherapy. Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the various monotherapies. Suitable anti-proliferative drugs or cytostatic compounds to be used in combination with the presently disclosed compounds include anti-cancer drugs. Numerous anti-cancer drugs which may be used are well known and include, but are not limited to: Acivicin; Aclarubicin; Acodazole Hydrochloride; Acronine; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azaribine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Bryostatin- 1 ; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Celebrex; Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Doxorubicin Glucuronide; Cyanomorpholino Doxorubicin; 2-Pyrrolinodoxorubicin (2P-DOX), Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflornithine Hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Epirubicin Glucuronide; Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine Phosphate Sodium; Etanidazole; Etoposide; Etoposide Phosphate; Etoposide Glucuronide; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine (FUdR); 3',5'-O-dioleoyl-FudR (FUdR-dO); Fludarabine; Fludarabine Phosphate; Fluorouracil; Fluorocitabine; Flutamide; Fluoxymesterone; Fosquidone; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydrochloride; Hydroxyurea; Hydroxyprogesterone caproate; Idarubicin; Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a; Interferon Alfa-2b; Interferon Alfa-nl; Interferon Alfa-n3; Interferon Beta-I a; Interferon Gamma-I b; Iproplatin; Irinotecan Hydrochloride; L-asparaginase; Lanreotide Acetate; Letrozole; Leucovorin; Leuprolide Acetate; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine; Mechlorethamine; Mechlorethamine Hydrochloride; Medroprogesterone acetate; Megestrol Acetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; 6- Mercaptopurine; Methotrexate; Methotrexate Sodium; Metoprine; Meturedepa; Mithramycin; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone; Mitoxantrone Hydrochloride; Mycophenolic Acid; Niraparib; Nocodazole; Nogalamycin; Olaparib; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Phenyl Butyrate, Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane; Porfimer Sodium; Porfiromycin; Prednimustine; Prednisone; Procarbazine; Procarbazine Hydrochloride; PSI-341, Puromycin; Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Rucaparib; Safingol; Safingol Hydrochloride; Semustine; Semustine Streptozocin; Simtrazene; Sparfosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Sulofenur; Talazoparib; Talisomycin; Taxol; Taxotere; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Topotecan; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Velaparib; Velcade; Verteporfin; Vinblastine; Vinblastine Sulfate; Vincristine; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine; Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; and Zorubicin Hydrochloride.

Other anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; acylfulvene; adecypenol; adozelesin; ALL-TK antagonists; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; anagrelide; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bisaziridinylspermine; bisnafide; bistratene A; bortezomib; breflate; budotitane; buthionine sulfoximine; calicheamicin; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxy amidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; daunomycin glucuronide; daunorubicin; dehydrodidemnin B; diethylstilbestrol; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; didemnin B; didox; diethylnor spermine; azacytidine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; ethinyl estradiol; etoposide phosphate; exemestane; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-I receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; irinotecan; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anti-cancer compound; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06- benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; osaterone; oxaliplatin; oxaunomycin; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinumtriamine complex; porfimer sodium; porfiromycin; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII re tinamide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofuran; SN-38; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen; tamoxifen methiodide; tauromustine; taxanes; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temozolomide; testosterone proprionate, tetrachlorodecaoxide; tetrazomine; thaliblastine; thalidomide; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; titanocene dichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; vinorelbine; vinxaltine; vitaxin; zanoterone; zilascorb; zinostatin stimalamer; abrin; ricine; ribonuclease; onconase; rapLRl; DNase I; Staphylococcal enterotoxin-A; pokeweed antiviral protein; gelonin; diphtheria toxin; Pseudomonas exotoxin; and Pseudomona endotoxin; or combinations of these.

In some embodiments, the drug to be used in combination with the disclosed compounds is selected from duocarmycin and its analogues, dolastatins, combretastatin, calicheamicin, N-acetyl-y- calicheamycin (CMC), a calicheamycin derivative, maytansine and analogues thereof, DM-I, auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), tubulysin, disorazole, the epothilones, Paclitaxel, docetaxel, Topotecan, echinomycin, estramustine, cemadotine, eleutherobin, methopterin, actinomycin, daunorubicin, the daunorubicin conjugates, mitomycin C, mitomycin A, vincristine, retinoic acid, camptothecin, a camptothecin derivative, SN38, maytansine, a derivative of the maytansinoid type, DM1, DM4, TK1, amanitin, a pyrrolobenzodiazepine, a pyrrolobenzodiazepine dimer, methotrexate, ilomedine, aspirin, an IMIDs, lenalidomide, pomalidomide.

The presently disclosed compounds can also be used in combination with any of the following treatments:

Therapy in combination with compounds targeting the androgen receptor, including androgen depletion approaches and antiandrogens. Such inhibitors include but are not limited to enzalutamide, apalutamide, darolutamide, etc.

Therapy in combination with inhibitors of Poly(ADP-ribose) polymerases (PARP), a class of chemotherapeutic agents directed at targeting cancers with defective DNA-damage repair (Yuan, et al., Expert Opin Ther Pat, 2017, 27: 363). Such PARP inhibitors include but are not limited to olaparib, rucaparib, velaparib, niraparib, talazoparib, pamiparib, iniparib, E7449, and A-966492. Therapy in combination with inhibitors of signaling pathways and mechanisms leading to repair of DNA single and double strand breaks as, e.g., nuclear factor-kappaB signaling (Pilie, et al., Nat Rev Clin Oncol, 2019, 16; 81 ; Zhang, et al., Chin J Cancer, 2012, 31 : 359). Such inhibitors include but are not limited to inhibitors of ATM and ATR kinases, checkpoint kinase 1 and 2, DNA- dependent protein kinase, and WEE1 kinase (Pilie, et al., Nat Rev Clin Oncol, 2019, 16; 81).

Therapy in combination with an immunomodulator (Khalil, et al., Nat Rev Clin Oncol, 2016, 13; 394), a cancer vaccine (Hollingsworth, et al., NPJ Vaccines, 2019, 4; 1), an immune checkpoint inhibitor (e.g., PD-1, PD-L1, CTLA-4-inhibitor) (Wei, et al., Cancer Discov, 2018, 8; 1069), a Cyclin-D-Kinase 4/6 inhibitor (Goel, et al., Trends Cell Biol, 2018, 28; 911), an antibody being capable of binding to a tumor cell and/or metastases and being capable of inducing antibodydependent cellular cytotoxicity (ADCC) (Kellner, et al., Transfus Med Hemother, 2017, 44; 327), a T cell- or NK cell engager (e.g., bispecific antibodies) (Yu, et al., J Cancer Res Clin Oncol, 2019, 145; 941), a cellular therapy using expanded autologous or allogeneic immune cells (e.g., chimeric antigen receptor T (CAR-T) cells) (Khalil, et al., Nat Rev Clin Oncol, 2016, 13; 394). Immune checkpoint inhibitors include, but are not limited to nivolumab, ipilimumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and cemiplimab.

According to the present disclosure, the compounds may be administered prior to, concurrent with, or following other anti-cancer compounds. The administration schedule may involve administering the different agents in an alternating fashion. In other embodiments, the compounds may be delivered before and during, or during and after, or before and after, or before and during and after treatment with other therapies. In some embodiments, the compound is administered more than 24 hours before the administration of the other anti -proliferative treatment. In some embodiments, more than one anti-proliferative therapy may be administered to a subject. For example, the subject may receive the present compounds, in combination with both surgery and at least one other anti-proliferative compound. In some embodiments, the compound may be administered in combination with more than one anti-cancer drug.

In some embodiments, the compounds of the present disclosure are used to detect cells and tissues overexpressing prostate specific membrane antigen (PSMA), whereby such detection is achieved by conjugating a detectable label to the compounds of the disclosure, for example a detectable radionuclide. In some embodiments, the cells and tissues detected are diseased cells and tissues and/or are either a or the cause for the disease and/or the symptoms of the disease, or are part of the pathology underlying the disease. In some embodiments, the diseased cells and tissues are causing and/or are part of an oncology indication (e.g., neoplasms, tumors, and cancers).

In some embodiments, the compounds of the present disclosure are used to treat cells and tissues overexpressing prostate specific membrane antigen (PSMA). In some embodiments, the cells and tissues treated are diseased cells and tissues and/or are either a or the cause for the disease and/or the symptoms of the disease, or are part of the pathology underlying the disease. In some embodiments, the diseased cells and tissues are causing and/or are part of an oncology indication (e.g., neoplasms, tumors, and cancers) and the therapeutic activity is achieved by conjugating a therapeutically active effector to the compounds of the present disclosure, for example, a therapeutically active radionuclide.

In a further embodiment, the compounds of the present disclosure are administered in therapeutically effective amounts. In some embodiments, a therapeutically effective amount is a dosage of the compound sufficient to provide a therapeutically or medically desirable result or effect in the subject to which the compound is administered. The therapeutically effective amount will vary with the particular condition being treated, the age and physical condition of the subject being treated, the severity of the condition, the duration of the treatment, the nature of the concurrent or combination therapy (if any), the specific route of administration and other factors within the knowledge and expertise of a healthcare practitioner. For example, in connection with methods directed towards treating subjects having a condition characterized by abnormal cell proliferation, an effective amount to inhibit proliferation would be an amount sufficient to reduce or halt altogether the abnormal cell proliferation so as to slow or halt the development of or the progression of a cell mass, such as, for example, a tumor. In an embodiment, and as preferably used herein, the term “inhibit” embraces all of the foregoing. In some embodiments, a therapeutically effective amount will be an amount necessary to extend the dormancy of micrometastases or to stabilize any residual primary tumor cells following surgical or drug therapy.

Generally, a therapeutically effective amount may vary based on factors, such as the subject’s age, condition, and sex, as well as the nature and extent of the disease in the subject, all of which can be determined by one of ordinary skill in the art. The dosage may be adjusted by the individual physician or veterinarian, particularly in the event of any complication. In some embodiments, a therapeutically effective amount includes, but not is limited to, an amount in a range from 0.1 pg/kg to about 2000 mg/kg, or from 1.0 pg/kg to about 1000 mg/kg, or from about 0.1 mg/kg to about 500 mg/kg, or from about 1.0 mg/kg to about 100 mg/kg, in one or more dose administrations daily, for one or more days. If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six, or more sub-doses, for example administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In some embodiments, the compounds are administered for more than 7 days, more than 10 days, more than 14 days, or more than 20 days. In some embodiments, the compound is administered over a period of weeks or months or years. In some embodiments, the compound is delivered on alternate days. For example, the agent is delivered every two days, or every three days, or every four days, or every five days, or every six days, or every week, or every month.

In some embodiments, the compounds of the present disclosure are for use in the treatment and/or prevention of a disease, whereby such treatment is radionuclide therapy.

For example, radionuclide therapy makes use of or is based on different forms of radiation emitted by a radionuclide. Such radiation can, for example, be any one of radiation of photons, radiation of electrons including but not limited to P" -particles and Auger-electrons, radiation of protons, radiation of neutrons, radiation of positrons, radiation of a-particles or an ion beam. Depending on the kind of particle or radiation emitted by said radionuclide, radionuclide therapy can, for example, be distinguished as photon radionuclide therapy, electron radionuclide therapy, proton radionuclide therapy, neutron radionuclide therapy, positron radionuclide therapy, a-particle radionuclide therapy or ion beam radionuclide therapy. All of these forms of radionuclide therapy are encompassed by the present disclosure, and all of these forms of radionuclide therapy can be realized by the compound of the disclosure, wherein a radionuclide attached to the compound of the disclosure, for example as an effector, is providing for this kind of radiation.

Radionuclide therapy preferably works by damaging the DNA of cells. The damage is caused by a photon, electron, proton, neutron, positron, a-particle or ion beam directly or indirectly ionizing the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA.

In the most common forms of radionuclide therapy, most of the radiation effect is through free radicals. Because cells have mechanisms for repairing DNA damage, breaking the DNA on both strands proves to be the most significant technique in modifying cell characteristics. Because cancer cells generally are undifferentiated and stem cell-like, they reproduce more, and have a diminished ability to repair sub-lethal damage compared to most healthy differentiated cells. The DNA damage is inherited through cell division, accumulating damage to the cancer cells, causing them to die or reproduce more slowly.

Oxygen is a potent radiosensitizer, increasing the effectiveness of a given dose of radiation by forming DNA-damaging free radicals. Therefore, use of high pressure oxygen tanks, blood substitutes that carry increased oxygen, hypoxic cell radiosensitizers such as misonidazole and metronidazole, and hypoxic cytotoxins, such as tirapazamine may be applied.

Other factors that are considered when selecting a radioactive dose include whether the patient is receiving chemotherapy, whether radiation therapy is being administered before or after surgery, and the degree of success of surgery.

The total radioactive dose may be fractionated, i.e., spread out over time in one or more treatments for one or more of several important reasons. For example, fractionation allows normal cells time to recover, while tumor cells are generally less efficient in repair between fractions. For example, fractionation also allows tumor cells that were in a relatively radio-resistant phase of the cell cycle during one treatment to cycle into a sensitive phase of the cycle before the next fraction is given. Similarly, tumor cells that were chronically or acutely hypoxic and, therefore, more radioresistant, may reoxygenate between fractions, improving the tumor cell kill.

It is generally known that different cancers respond differently to radiation therapy. The response of a cancer to radiation is described by its radiosensitivity. Highly radiosensitive cancer cells are rapidly killed by modest doses of radiation. These include leukemias, most lymphomas, and germ cell tumors.

It is important to distinguish radiosensitivity of a particular tumor, which to some extent is a laboratory measure, from “curability” of a cancer by an internally delivered radioactive dose in actual clinical practice. For example, leukemias are not generally curable with radiotherapy, because they are disseminated through the body. Lymphoma may be radically curable if it is localized to one area of the body. Similarly, many of the common, moderately radioresponsive tumors can be treated with curative doses of radioactivity if they are at an early stage. This applies, for example, to non-melanoma skin cancer, head and neck cancer, non-small cell lung cancer, cervical cancer, anal cancer, and prostate cancer.

The response of a tumor to radiotherapy is also related to its size. For complex reasons, very large tumors do not respond as well to radiation as smaller tumors or microscopic disease. Various strategies are used to overcome this effect. The most common technique is surgical resection prior to radiotherapy. This is most commonly seen in the treatment of breast cancer with wide local excision or mastectomy followed by adjuvant radiotherapy. Another method is to shrink the tumor with neoadjuvant chemotherapy prior to radical radionuclide therapy. A third technique is to enhance the radiosensitivity of the cancer by giving certain drugs during a course of radiotherapy. Examples of radiosensiting drugs include, but are not limited to Cisplatin, Nimorazole, and Cetuximab.

Introperative radiotherapy is a special type of radiotherapy that is delivered immediately after surgical removal of the cancer. This method has been employed in breast cancer (TARGeted Introperative radioTherapy), brain tumors and rectal cancers. Radionuclide therapy is in itself painless. Many low-dose palliative treatments cause minimal or no side effects. Treatment with higher doses may cause varying side effects during treatment (acute side effects), in the months or years following treatment (long-term side effects), or after retreatment (cumulative side effects). The nature, severity, and longevity of side effects depends on the organs that receive the radiation, the treatment itself (type of radionuclide, dose, fractionation, concurrent chemotherapy), and the patient.

It is within the present disclosure that the method for the treatment of a disease of the invention may realize each and any of the above strategies which are as such known in the art, and which insofar constitute further embodiments of the disclosure.

It is also within the present disclosure that the compound of the disclosure is used in a method for the diagnosis of a disease as disclosed herein. In some embodiments, such a method comprises the step of administering to a subject in need thereof a diagnostically effective amount of the compound of the disclosure.

In accordance with the present disclosure, an imaging method is selected from the group consisting of scintigraphy, Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), computed tomography (CT), and combinations thereof.

Scintigraphy is a form of diagnostic test or method used in nuclear medicine, wherein radiopharmaceuticals are internalized by cells, tissues and/or organs, for example, internalized in vivo, and radiation emitted by said internalized radiopharmaceuticals is captured by external detectors (gamma cameras) to form and display two-dimensional images. In contrast thereto, SPECT and PET forms and displays three-dimensional images. Because of this, SPECT and PET are classified as separate techniques to scintigraphy, although they also use gamma cameras to detect internal radiation. Scintigraphy is unlike a diagnostic X-ray where external radiation is passed through the body to form an image.

Single Photon Emission Tomography (SPECT) scans are a type of nuclear imaging technique using gamma rays. They are very similar to conventional nuclear medicine planar imaging using a gamma camera. Before the SPECT scan, the patient is injected with a radiolabeled chemical emitting gamma rays that can be detected by the scanner. A computer collects the information from the gamma camera and translates this into two-dimensional cross-sections. These crosssections can be added back together to form a three-dimensional image of an organ or a tissue. SPECT involves detection of gamma rays emitted singly, and sequentially, by the radionuclide provided by the radiolabeled chemical. To acquire SPECT images, the gamma camera is rotated around the patient. Projections are acquired at defined points during the rotation, typically every 3 - 6 degrees. In most cases, a full 360 degree rotation is used to obtain an optimal reconstruction. The time taken to obtain each projection is also variable, but 15 - 20 seconds is typical. This gives a total scan time of 15 - 20 minutes. Multi -headed gamma cameras are faster. Since SPECT acquisition is very similar to planar gamma camera imaging, the same radiopharmaceuticals may be used.

Positron Emitting Tomography (PET) is a non-invasive, diagnostic imaging technique for measuring the biochemical status or metabolic activity of cells within the human body. PET is unique since it produces images of the body's basic biochemistry or functions. Traditional diagnostic techniques, such as X-rays, CT scans, or MRI, produce images of the body's anatomy or structure. The premise with these techniques is that any changes in structure or anatomy associated with a disease can be seen. Biochemical processes are also altered by a disease, and may occur before any gross changes in anatomy. PET is an imaging technique that can visualize some of these early biochemical changes. PET scanners rely on radiation emitted from the patient to create the images. Each patient is given a minute amount of a radioactive pharmaceutical that either closely resembles a natural substance used by the body or binds specifically to a receptor or molecular structure. As the radioisotope undergoes positron emission decay (also known as positive beta decay), it emits a positron, the antiparticle counterpart of an electron. After traveling up to a few millimeters, the positron encounters an electron and annihilates, producing a pair of annihilation (gamma) photons moving in opposite directions. These are detected when they reach a scintillation material in the scanning device, creating a burst of light, which is detected by photomultiplier tubes or silicon avalanche photodiodes. The technique depends on simultaneous or coincident detection of the pair of photons. Photons that do not arrive in pairs, i.e., within a few nanoseconds, are ignored. All coincidences are forwarded to the image processing unit where the final image data is produced using image reconstruction procedures.

SPECT/CT and PET/CT is the combination of SPECT and PET with computed tomography (CT). The key benefits of combining these modalities are improving the reader’s confidence and accuracy. With traditional PET and SPECT, the limited number of photons emitted from the area of abnormality produces a very low-level background that makes it difficult to anatomically localize the area. Adding CT helps determine the location of the abnormal area from an anatomic perspective and categorize the likelihood that this represents a disease.

It is within the present disclosure that the method for the diagnosis of a disease of the disclosure may realize each and any of the above strategies which are as such known in the art, and which insofar constitute further embodiments of the disclosure.

In some embodiments, compounds of the present disclosure can be useful to stratify patients, i.e., to create subsets within a patient population that provide more detailed information about how the patient will respond to a given drug. Stratification can be a critical component to transforming a clinical trial from a negative or neutral outcome to one with a positive outcome by identifying the subset of the population most likely to respond to a novel therapy.

Stratification includes the identification of a group of patients with shared “biological” characteristics to select the optimal management for the patients and achieve the best possible outcome in terms of risk assessment, risk prevention and achievement of the optimal treatment outcome.

In some embodiments, a compound of the present disclosure may be used to assess or detect, a specific disease as early as possible (which is a diagnostic use), the risk of developing a disease (which is a susceptibility/risk use), the evolution of a disease including indolent vs. aggressive (which is a prognostic use) and it may be used to predict the response and the toxicity to a given treatment (which is a predictive use).

It is also within the present disclosure that the compounds of the disclosure may be used in a theragnostic method. The concept of theragnostics is to combine a therapeutic agent with a corresponding diagnostic test that can increase the clinical use of the therapeutic drug. The concept of theragnostics is becoming increasingly attractive and is widely considered the key to improving the efficiency of drug treatment by helping doctors identify patients who might profit from a given therapy and hence avoid unnecessary treatments.

The concept of theragnostics is to combine a therapeutic agent with a diagnostic test that allows doctors to identify those patients who will benefit most from a given therapy. In an embodiment, a compound of the present disclosure is used for the diagnosis of a patient, i.e., identification and localization of the primary tumor mass as well as potential local and distant metastases. Furthermore, the tumor volume can be determined, especially utilizing three-dimensional diagnostic modalities such as SPECT or PET. Only those patients having PSMA-positive tumor masses and who, therefore, might profit from a given therapy are selected for a particular therapy and hence unnecessary treatments are avoided. For example, such therapy is a PSMA targeted therapy using a compound of the present disclosure. In some embodiments, chemically identical tumor-targeted diagnostics, including, for example, imaging diagnostics for scintigraphy, PET or SPECT and radiotherapeutics are applied. Such compounds only differ in the radionuclide and therefore usually have a very similar if not identical pharmacokinetic profile. This can be realized using a chelator and a diagnostic or therapeutic radiometal. Alternatively, this can be realized using a precursor for radiolabeling and radiolabeling with either a diagnostic or a therapeutic radionuclide. In one embodiment diagnostic imaging is used by means of quantification of the radiation of the diagnostic radionuclide and subsequent dosimetry which is known to those skilled in the art and the prediction of drug concentrations in the tumor compared to vulnerable side effect organs. Thus, a truly individualized drug dosing therapy for the patient is achieved.

In some embodiments, the theragnostic method is realized with only one theragnostically active compound such as a compound of the present disclosure labeled with a radionuclide emitting diagnostically detectable radiation (e.g., positrons or gamma rays) as well as therapeutically effective radiation (e.g., electrons or alpha particles).

The disclosure also contemplates a method of intraoperatively identifying/disclosing diseased tissues expressing PSMA in a subject. Such method uses a compound of the disclosure, whereby in some embodiments such compound of the disclosure comprises as the effector a diagnostically active agent such as a diagnostically active radionuclide.

According to a further embodiment of the disclosure, the compound of the disclosure, particularly if complexed with a radionuclide, may be employed as adjunct or adjuvant to any other tumor treatment including, surgery as the primary method of treatment of most isolated solid cancers, radiation therapy involving the use of ionizing radiation in an attempt to either cure or improve the symptoms of cancer using either sealed internal sources in the form of brachytherapy or external sources, chemotherapy such as alkylating agents, antimetabolites, anthracy clines, plant alkaloids, topoisomerase inhibitors, and other antitumor agents, hormone treatments that modulate tumor cell behavior without directly attacking those cells, targeted agents which directly target a molecular abnormality in certain types of cancer including monoclonal antibodies and tyrosine kinase inhibitors, angiogenesis inhibitors, immunotherapy, cancer vaccination, palliative care including actions to reduce the physical, emotional, spiritual, and psycho-social distress to improve the patient's quality of life and alternative treatments including a diverse group of health care systems, practices, and products that are not part of conventional medicine.

In an embodiment of the methods of the disclosure, the subject is a patient. In an embodiment, a patient is a subject which has been diagnosed as suffering from or which is suspected of suffering from or which is at risk of suffering from or developing a disease, whereby the disease is a disease as described herein, a disease involving prostate specific membrane antigen (PSMA).

Dosages employed in practicing the methods for treatment and diagnosis, respectively, where a radionuclide is used and more specifically attached to or part of the compound of the disclosure will vary depending, e.g., on the particular condition to be treated, for example the known radiosensitivity of the tumor type, the volume of the tumor and the therapy desired. In general, the dose is calculated on the basis of radioactivity distribution to each organ and on observed target uptake. A y-emitting complex may be administered once or at several times for diagnostic imaging. In animals, an indicated dose range may be, for example, from 0.1 ng/kg to 5 mg/kg of the compound of the disclosure complexed, e.g., with 1 kBq to 200 MBq of a y-emitting radionuclide, including, but not limited to, ⁱⁿ In or ⁸⁹ Zr. An a- or P-emitting complex of the compound of the disclosure may be administered at several time points, e.g., over a period of 1 to 3 weeks or longer. In animals, an indicated dosage range may be, for example, from 0.1 ng/kg to 5 mg/kg of the compound of the disclosure complexed, e.g., with 1 kBq to 200 MBq of an a- or P-emitting radionuclide, including, but not limited to, ²²⁵ Ac or ¹⁷⁷ Lu. In larger mammals, including, for example, humans, an indicated dosage range may be, for example, from 0.1 ng/kg to 5 mg/kg or for example 0.1 ng/kg to 100 pg/kg of the compound of the disclosure complexed with, e.g., 10 to 1000 MBq of a y-emitting radionuclide, including, but not limited to, ⁱⁿ In or ⁸⁹ Zr. In larger mammals, including, for example, humans, an indicated dosage range may be, for example, from 0.1 ng/kg to 5 mg/kg or for example, from 0.1 ng/kg to 100 pg/kg of the compound of the disclosure complexed with, e.g., 1 to 100000 MBq of an a- or P-emitting radionuclide, including, but not limited to, ²²⁵ Ac or ¹⁷⁷ Lu.

In certain embodiments, uptake can be measured in terms of absorbed dose (mGy/MBq), SUVmax, SUVmean. In animals, uptake across tissues is reported in injected dose/gram ID/g. Sensitivity to radiation is tumor and non-tumor tissue dependent. The favorable tumor to non-tumor tissue uptake of the present compounds allows delivery of a radioactive nuclide at a dose that could reduce tumor growth, or partially or completely destroys the tumor. At such dose, no permanent or critical damage to non-tumor tissue is expected.

In a further aspect, the instant disclosure is related to a composition and a pharmaceutical composition in particular, comprising the compound of the disclosure.

The pharmaceutical composition of the present disclosure comprises at least one compound of the disclosure and, optionally, one or more carrier substances, excipients and/or adjuvants. The pharmaceutical composition may additionally comprise, for example, one or more of water, buffers such as, e.g., neutral buffered saline or phosphate buffered saline, ethanol, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates such as e.g., glucose, mannose, sucrose or dextrans, mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives. Furthermore, one or more other active ingredients may, but need not, be included in the pharmaceutical composition of the disclosure. The pharmaceutical composition of the disclosure may be formulated for any appropriate route of administration, including, for example, topical such as, e.g., transdermal or ocular, oral, buccal, nasal, vaginal, rectal or parenteral administration. In an embodiment, and as preferably used herein, the term parenteral includes subcutaneous, intradermal, intravascular such as, e.g., intravenous, intramuscular, intrathecal and intraperitoneal injection, as well as any similar injection or infusion technique. In some embodiments, the route of administration is intravenous administration.

In an embodiment of the disclosure the compound of the disclosure comprising a radionuclide is administered by any conventional route, in particular intravenously, e.g., in the form of injectable solutions or suspensions. The compound of the disclosure may also be administered advantageously by infusion, e.g., by an infusion of 30 to 60 min.

In some embodiments, depending on the site of the tumor, the compound of the disclosure may be administered as close as possible to the tumor site, e.g., by means of a catheter. Such administration may be carried out directly into the tumor tissue or into the surrounding tissue or into the afferent blood vessels. The compound of the disclosure may also be administered repeatedly in doses, including, in some embodiments, in divided doses.

According to an embodiment of the disclosure, a pharmaceutical composition of the disclosure comprises a stabilizer, e.g., a free radical scavenger, which inhibits autoradiolysis of the compound of the disclosure. Suitable stabilizers include, e.g., serum albumin, ascorbic acid, retinol, gentisic acid or a derivative thereof, or an amino acid infusion solution such, e.g., used for parenteral protein feeding, for example, free from electrolyte and glucose, for example a commercially available amino acid infusion such as Proteinsteril® KE Nephro. In some embodiments, ascorbic acid and gentisic acid are used.

A pharmaceutical composition of the disclosure may comprise further additives, e.g., an agent to adjust the pH between 7.2 and 7.4, e.g., sodium or ammonium acetate or Na2HP04. In some embodiments, the stabilizer is added to the non-radioactive compound of the disclosure and introduction of the radionuclide, for instance the complexation with the radionuclide, is performed in the presence of the stabilizer, either at room temperature or, for example, at a temperature of from 40 to 120° C. The complexation may conveniently be performed under air free conditions, e.g., under N2 or Ar. In some embodiments, further stabilizer may be added to the composition after complexation.

Excretion of the compound of the disclosure, particularly if the effector is a radionuclide, essentially takes place through the kidneys. In some embodiments, further protection of the kidneys from radioactivity accumulation may be achieved by administration of lysine or arginine or an amino acid solution having a high content of lysine and/or arginine, e.g., a commercially available amino acid solution such as Synthamin®-14 or -10, prior to the injection of or together with the compound of the disclosure, particularly if the effector is a radionuclide. In some embodiments, protection of the kidneys may also be achieved by administration of plasma expanders, such as, e.g., gelofusine, either instead of or in addition to amino acid infusion. In some embodiments, protection of the kidneys may also be achieved by administration of diuretics providing a means of forced diuresis which elevates the rate of urination. Such diuretics include high ceiling loop diuretics, thiazides, carbonic anhydrase inhibitors, potassium-sparing diuretics, calcium-sparing diuretics, osmotic diuretics and low ceiling diuretics. In some embodiments, a pharmaceutical composition of the disclosure may contain, apart from a compound of the disclosure, at least one of these further compounds intended for or suitable for kidney protection, including, for example, kidney protection of the subject to which the compound of the disclosure is administered.

It will be understood by a person skilled in the art that the compounds of the disclosure are disclosed herein for use in various methods. It will be further understood by a person skilled in the art that the composition of the disclosure and the pharmaceutical composition of the disclosure can be equally used in said various methods. It will also be understood by a person skilled in the art that the composition of the disclosure and the pharmaceutical composition are disclosed herein for use in various methods. It will be equally understood by a person skilled in the art that the compounds of the disclosure can be equally used in said various methods.

It will be acknowledged by a person skilled in the art that the composition and/or the pharmaceutical composition as disclosed herein may contain one or more further compounds in addition to the compound of the disclosure. To the extent that such one or more further compounds are disclosed herein as being part of the composition of the disclosure and/or of the pharmaceutical composition of the disclosure, it will be understood that such one or more further compounds can be administered separately from the compound of the disclosure to the subject which is exposed to or the subject of a method of the disclosure. Such administration of the one or more further compounds can be performed prior to, concurrently with or after the administration of the compound of the invention. It will also be acknowledged by a person skilled in the art that in a method of the invention, apart from a compound of the invention, one or more further compounds may be administered to a subject. Such administration of the one or more further compounds can be performed prior to, concurrently with or after the administration of the compound of the disclosure. To the extent that such one or more further compounds are disclosed herein as being administered as part of a method of the disclosure, it will be understood that such one or more further compounds are part of a composition of the disclosure and/or of a pharmaceutical composition of the disclosure. It is within the present disclosure that the compound of the disclosure and the one or more further compounds may be contained in the same or a different formulation. It is also within the present disclosure that the compound of the disclosure and the one or more further compounds are not contained in the same formulation, but are contained in the same package containing a first formulation comprising a compound of the disclosure, and a second formulation comprising the one or more further compounds, whereby the type of formulation may be the same or may be different.

It is within the present disclosure that more than one type of a compound of the disclosure may be contained in the composition of the disclosure and/or the pharmaceutical composition of the disclosure. It is also within the present disclosure that more than one type of a compound of the disclosure may be used, preferably administered, in a method of the disclosure.

It will be acknowledged that a composition of the disclosure and a pharmaceutical composition of the disclosure may be manufactured in conventional manner.

Radiopharmaceuticals have decreasing content of radioactivity with time, as a consequence of the radioactive decay. The physical half-life of the radionuclide is often short for radiopharmaceutical diagnostics. In these cases, the final preparation has to be done shortly before administration to the patient. This is in particular the case for positron emitting radiopharmaceuticals for tomography (PET radiopharmaceuticals). It often leads to the use of semi-manufactured products such as radionuclide generators, radioactive precursors and kits.

In some embodiments, a kit of the disclosure comprises apart from one or more than one compounds of the disclosure typically at least one of the followings: instructions for use, final preparation and/or quality control, one or more optional excipient(s), one or more optional reagents for the labeling procedure, optionally one or more radionuclide(s) with or without shielded containers, and optionally one or more device(s), whereby the device(s) is/are selected from the group comprising a labeling device, a purification device, an analytical device, a handling device, a radioprotection device or an administration device.

Shielded containers known as "pigs" for general handling and transport of radiopharmaceutical containers come in various configurations for holding radiopharmaceutical containers such as bottles, vials, syringes, etc. One form includes a removable cover that allows access to the held radiopharmaceutical container. When the pig cover is in place, the radiation exposure is acceptable.

In some embodiments, a labeling device is selected from the group of open reactors, closed reactors, microfluidic systems, nanoreactors, cartridges, pressure vessels, vials, temperature controllable reactors, mixing or shaking reactors and combinations thereof.

In some embodiments, a purification device is selected from the group of ion exchange chromatography columns or devices, size-exclusion chromatography columns or devices, affinity chromatography columns or devices, gas or liquid chromatography columns or devices, solid phase extraction columns or devices, filtering devices, centrifugations vials columns or devices and combinations thereof.

In some embodiments, an analytical device is selected from the group of tests or test devices to determine the identity, radiochemical purity, radionuclidic purity, content of radioactivity and specific radioactivity of the radiolabelled compound and combinations thereof. In some embodiments, a handling device is selected from the group consisting of devices for mixing, diluting, dispensing, labeling, injecting and administering radiopharmaceuticals to a subject and combinations thereof.

In some embodiments, a radioprotection device is used in order to protect doctors and other personnel from radiation when using therapeutic or diagnostic radionuclides. In some embodiments, the radioprotection device is selected from the group consisting of devices with protective barriers of radiation-absorbing material selected from the group consisting of aluminum, plastics, wood, lead, iron, lead glass, water, rubber, plastic, cloth, devices ensuring adequate distances from the radiation sources, devices reducing exposure time to the radionuclide, devices restricting inhalation, ingestion, or other modes of entry of radioactive material into the body and devices providing combinations of these measures.

In some embodiments, an administration device is selected from the group of syringes, shielded syringes, needles, pumps, and infusion devices and combinations thereof Syringe shields are commonly hollow cylindrical structures that accommodate the cylindrical body of the syringe and are constructed of lead or tungsten with a lead glass window that allows the handler to view the syringe plunger and liquid volume within the syringe.

EXAMPLES

The following Examples have been included to provide guidance to one of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill can appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. The synthetic descriptions and specific examples that follow are only intended for the purposes of illustration, and are not to be construed as limiting in any manner to make compounds of the disclosure by other methods.

Abbreviations used in the instant application and the following examples in particular are as follows:

Example 1: Material and Methods

The materials and methods as well as general methods are further illustrated by the following examples.

Solvents:

Solvents were used in the specified quality without further purification. Acetonitrile (Super Gradient, HPEC, VWR - for analytical purposes; PrepSolv, Merck - for preparative purposes); cyclohexane; dichloromethane (synthesis grade, Roth); dimethyl sulfoxide (BioScience grade, Roth) A,A-dimethylformamide (peptide synthesis grade, Biosolve); methanol (synthesis grade, Roth); methyl-/er/-butylether (synthesis grade, Roth); tetrahydrofuran (puriss. grade, Sigma- Aldrich).

Water: Milli-Q Plus, Millipore, demineralized. Chemicals:

Chemicals were synthesized according to or in analogy to literature procedures or purchased from Sigma-Aldrich-Merck (Deisenhofen, Germany), Bachem (Bubendorf, Switzerland),— VWR (Darmstadt, Germany), Novabiochem (Merck Group, Darmstadt, Germany), Iris Biotech (Marktredwitz, Germany), CheMatech (Dijon, France), Roth (Karlsruhe, Deutschland), or other companies and used in the assigned quality without further purification.

HPLC/MS analyses

HPLC/MS analyses were performed by injection of 5 pl of a solution of the sample, using a 2-step gradient for all chromatograms (5-65% B in 12 min, followed by 65-90% in 0.5 min, A: 0.1% TFA in water and B: 0.1% TFA in ACN). RP columns were from Agilent (Type Poroshell 120, 2.7pm, EC-C18, 50 x 3.00 mm, flow 0.8 ml, HPLC at room temperature); Mass spectrometer: Agilent 6230 LC/TOF-MS, ESI ionization. MassHunter Qualitative Analysis B.07.00 SP2 was used as software. UV detection was done at X = 230 nm. Retention times (R _t ) are indicated in the decimal system (e.g., 1.9 min = 1 min 54 s) and are referring to detection in the UV spectrometer. The accuracy of the mass spectrometer was approx. ± 5 ppm.

Preparation of compounds:

Specific embodiments for the preparation of compounds of the disclosure are provided in the following examples. Unless otherwise specified, all starting materials and reagents are of standard commercial grade, and are used without further purification, or are readily prepared from such materials by routine methods. Those skilled in the art of organic synthesis will recognize in light of the instant disclosure that starting materials and reaction conditions may be varied including additional steps employed to produce compounds encompassed by the present disclosure. Example 2: Synthesis of PSM-01 (Formula 24)

Formula 24

The entire synthesis of PSM-01 was performed as solid phase synthesis on a polystyrene resin (crosslinked with 1% 1 ,4-divinylbenzene) with a 4-benzyloxybenzyl alcohol (Wang) linker according to the synthesis scheme shown in Figure 1.

Manual steps were performed in plastic syringes equipped with frits (material PE, Roland Vetter Laborbedarf OHG, Ammerbuch, Germany).

Manual resin loading:

Loading of the first amino acid, i.e. Alloc -L-Lys(Fmoc)-OH onto Wang resin was performed manually, essentially according to the l-(mesitylene-2-sulfonyl)-3-nitro-l,2,4-triazole (MSNT) / /V-methyl imidazole (Melm) method as described in the Novabiochem catalog (Novabiochem. Peptide Synthesis; Novabiochem: Darmstadt, Germany, 2014/2015). Briefly, Wang resin (initial loading: 0.99 mmol/g, 250 mg, 0.25 mmol, 1 eq.) in a fritted syringe was swollen in DCM (5 ml) for 30 minutes and subsequently washed with DCM (3 ml, 1 minute). To a stirring suspension of Alloc-Lys(Fmoc)-OH (566 mg, 1.25 mmol, 5 eq.) in dry DCM (3.5 ml) containing 3 drops of dry tetrahydrofuran, was added /V-methyl imidazole (74 pl, 0.94 mmol, 3.75 eq.) followed by 1- (mesitylene-2-sulfonyl)-3-nitro-l,2,4-triazole (370 mg, 1.25 mmol, 5 eq.). After turning clear, the reaction mixture was transferred to the resin and agitated for 4 hours. Afterwards, the resin was washed with DCM (5 ml, 5 x 1 minute) and DMF (5 ml, 5 x 1 minute). Capping of unreacted groups was performed by reaction with a mixture of DIPEA (522 pl, 3 mmol, 12 eq.) and acetic anhydride (284 pl, 3 mmol, 12 eq.) in DMF (5 ml) for 10 minutes. Afterwards, the resin was washed with DMF (5 ml, 3 x 1 minute) and DCM (5 ml, 3 x 1 minute), and dried in vacuo.

Resin loading was estimated by cleaving the Fmoc group from the resin bound Alloc-Eys(Fmoc)- OH with piperidine and photometerical determination of the resulting dibenzofulvene -piperidine adduct. The complete resin was treated with 20% piperidine in DMF (3 mF, 2 and 20 min) and then washed with 20% piperidine in DMF (2mE, 2x 1 min). After diluting the resulting combined piperdine/DMF solution by a factor of 300, a UV spectrum was recorded with a Molecular Devices SpectraMax M5 UV/VIS spectrometer using a quartz cuvette as sample holder. The absorption value of the 301 nm absorption maximum (molar absorption coefficient e = 8021 E x mol ¹ x cm' ¹ according to S. Eissler et al. J Pept Sci, 2017, 23(10), 757) was used for calculation of the dibenzofulvene -piperidine adduct concentration in the Fmoc cleavage solution. The determined resin loading was 0.175 mmol, i.e. ~0.5 mmol/g.

Automated solid phase synthesis:

Automated solid phase synthesis was performed on a Tetras Peptide Synthesizer (Advanced ChemTech).

Consecutive cycles of Fmoc deprotection followed by building block coupling were performed in an automated fashion in order to synthesize the polyamide chain on the lysine side chain. This comprises the coupling reactions of A-Fmoc-3-(2-naphthyl)-L-alanine, A-Fmoc-tranexamic acid, and DOTA(tBu)3-OH in this order.

Fmoc deprotection:

After swelling in DMF, the resin was washed with DMF and then treated with 20 % piperidine in DMF (3 ml, 2 and 20 minutes) and subsequently washed with DMF (3 ml, 5 x 1 minute).

Coupling of building blocks/amino acids (chain assembly): For a coupling reaction, the resin (0.175 mmol, 1 eq.) was agitated in a solution of the building block (0.7 mmol, 4 eq.), DIPEA (1.4 mmol, 8 eq.), and HATU (0.7 mmol, 4 eq.) in DMF (5 ml) for 45 min. Coupling of DOTA(tBu)3-OH was performed for 3 h , whereof the second half was in the presence of supplemented A,AAIi isopropylcarbodi imide (1.75 mmol, 10 eq.). After reaction, the resin was washed with DMF (3 ml, 5 x 1 minute).

Alloc deprotection:

After swelling in DMF, the resin was washed with DMF and DCM. DCM was de-oxygenated by passing a stream of nitrogen through the stirred solvent. The oxygen-free solvent was used to wash the resin trice. Then 2 ml of a 2 M solution of 1,3 -dimethylbarbituric acid in oxygen-free DCM and 1 ml of a 25 mM solution of tetrakis(triphenylphosphine)palladium(0) in oxygen-free DCM were added to the resin. The resin was agitated for 1 hour and then washed with DCM, methanol, DMF, 5% DIPEA in DMF, 5% sodium diethyldi thiocarbamate in DMF, DMF and DCM (each washing step was repeated 3 times with 5 ml, 1 minute).

Urea synthesis:

For urea synthesis, the resin was swollen in DCM (5 ml), then washed once with DCM (3 ml). A suspension of A,A'-disuccinimidyl carbonate (DSC, 448 mg, 1.7 mmol, 10 eq.) and triethylamine (277 pl, 2 mmol, 11.5 eq.) in DCM (6 ml) was added, and agitated for 4 hours at room temperature. Afterwards, the reactor was drained, and the resin was washed with DCM, and DMF (each washing step was repeated 3 times with 5 ml, 1 minute). In a second step, the formed O-succinimidyl carbamate was reacted with a suspension of L-quisqualic acid (66 mg, 0.35 mmol, 2 eq.) and DIPEA (152 pl, 0.875 mmol, 5 eq.) in DMF (6 ml) for 4 h at 50°C followed by washes in DMF and DCM (each washing step was repeated 3 times with 5 ml, 1 minute).

Cleavage from solid phase and final deprotection:

After completion of the assembly, the resin was finally washed with DCM (3 ml, 4 x 1 minute), dried in vacuo overnight, and treated with TFA, EDT, water, and TIPS (94/2.5/2.5/1) for 4 h. Afterwards, the cleavage solution was poured into a chilled mixture of MTBE and cyclohexane (1/1, 10-fold excess compared to the volume of cleavage solution), centrifuged at 4 °C for 5 minutes and the precipitate collected and dried in the vacuum. The residue was lyophilized from water/acetonitrile prior to purification or further modification.

Preparative HPLC:

PSM-01 was purified by preparative HPLC. Preparative HPLC separations were done with a reversed phase column (Kinetex 5p XB-C18 100 A, 150 x 30 mm from Phenomenex, 100 A, 150 x 25 mm) as stationary phase. As mobile phase, 0.1% TFA in water (A) and 0.1% TFA in ACN (B) were used which were mixed in linear binary gradients. A linear gradient from 10% B (and correspondingly 90% A) to 30% B (and correspondingly 70% A) was run within 30 min at a flowrate of 30 ml/min. Fractions containing the pure product were pooled and freeze dried.

PSM-01. White solid. Yield: 33.4 mg (30.8 pmol, 18 % of theory, based on Alloc-Lys(Fmoc)- OH-loaded resin). HPLC: R _t = 5.2 min. LC/TOF-MS (m/z for [M+H] ⁺ ): found 1084.498 (calculated 1084.498). C49H69N11O17 (MW = 1084.138).

Alterations in the synthetic procedure:

The following alterations have also been implemented in the successful synthesis of PSM-01 :

• use of 2-chlorotrityl chloride resin instead of Wang resin

• loading of Dde-Lys(Fmoc)-OH instead of Alloc-Lys(Fmoc)-OH (requiring replacement of the later Alloc deprotection step by Dde deprotection by treatment with 2% hydrazine in DMF)

• replacing the DSC activation step for urea synthesis by treatment with 4-nitrophenyl chloroformate and pyridine in DCM

Example 3: Preparation of DOTA-transition metal complexes of compounds of the disclosure

General procedure for the preparation of compounds comprising DOTA-transition metalcomplexes from PSM-01: A 0.1 mM solution of PSM-01 featuring uncomplexed DOTA (20 mg, 18.45 pmol) in 0.4 M sodium acetate, pH = 5 was diluted with a solution of 0.1 mM solution of the corresponding metal salt in water whereby the molar ratio of PSM-01 to metal was adjusted to 1 : 3. The solution was stirred at 50 °C for 20 minutes. The solution was then applied to solid phase extraction. For solid phase extraction, 150 mg Varian Bondesil-ENV was placed in a 5 ml polystyrene syringe, prewashed with methanol (3 x 2 ml) and water (3 x 2 ml). Then the reaction solution was applied to the column. Thereafter elution was performed with water (3 x 2 ml - to remove excess salt), 2 ml of 50% ACN in water as first fraction and each of the next fractions were eluted with 2 ml of 50% ACN in water containing 0.1% TFA. Fractions containing the pure product were pooled and freeze dried.

PSM-02 (Lutetium complexed PSM-01) was prepared starting from PSM-01 and LuCL. White solid. Yield: 19.1 mg (15.2 pmol, 82 % of theory). HPLC: Rt = 5.2 min. LC/TOF-MS (m/z for [M+H] ⁺ ): found 1256.408 (calculated 1256.408). C49H66LUN11O17 (MW = 1256.080).

PSM-03 (Indium complexed PSM-01) was prepared starting from PSM-01 and InCh 4 H2O. White solid. Yield: 7.0 mg (5.9 pmol, 32 % of theory). HPLC: R _t = 5.1 min. LC/TOF-MS (m/z for [M+H] ⁺ ): found 1196.374 (calculated 1196.373). C ₄ 9H ₆ 6lnNiiOi7 (MW = 1195.932).

PSM-04 (Gallium complexed PSM-01) was prepared starting from PSM-01 and Ga(NOs)3 H2O. White solid. Yield: 12.1 mg (10.5 pmol, 57 % of theory). HPLC: Rt = 5.5 min. LC/TOF-MS (m/z for [M+H] ⁺ ): found 1150.393 (calculated 1150.394). C ₄₉ H ₆ 6GaNnOi7 (MW = 1150.837).

Example 4: Synthesis of PSM-05 (Formula 25)

Formula 25

The synthesis of PSM-05 was performed according to the synthetic procedure as described for PSM-01 in Example 2, with the following alterations:

♦ The synthesis started from Wang resin loaded with 80 pmol Alloc -L-Eys(Fmoc)-OH.

♦ For amide coupling of the building blocks, the resin was reacted with a solution of the building block (0.4 mmol, 5 eq.), DIPEA (0.8 mmol, 10 eq.), and HATU (0.4 mmol, 5 eq.) in DMF (2 ml) for 45 min. Instead of DOTA(tBu)3-OH, DOTA-GA(tBu)4-OH (0.24 mmol, 3 eq.) was employed in reaction with DIPEA (0.48 mmol, 6 eq.), and HATU (0.24 mmol, 3 eq.) in DMF (2 ml) for 3h , whereof the second half was in the presence of supplemented A,A'-diisopropylcarbodiimide (0.64 mmol, 8 eq.).

♦ The reaction with quisqualic acid of the O-succinimidyl carbamate was performed twice.

♦ PSM-05 was purified by preparative HPEC using a gradient from 15% B to 30% B in 30 min at a flow rate of 30 ml/min.

PSM-05. White solid. Yield: 6.01 mg (5.2 pmol, 6 % of theory, based on Alloc-Lys(Fmoc)-OH- loaded resin). HPLC: Rt = 5.2 min. LC/TOF-MS (m/z for [M+H] ⁺ ): found 1156.572 (calculated 1156.516). C52H73N11O19 (MW = 1156.200). Example 5: Synthesis of PSM-06 (Formula 26)

Formula 26

The synthesis of PSM-06 was performed according to the synthetic procedure as described for PSM-01 in Example 2, with the following alterations:

♦ The synthesis started from Wang resin loaded with 50 pmol Alloc -L-Lys(Fmoc)-OH.

♦ For amide coupling of the building blocks, the resin was reacted with a solution of the building block (0.25 mmol, 5 eq.), DIPEA (0.5 mmol, 10 eq.), and HATU (0.25 mmol, 5 eq.) in DMF (2.15 ml) for 45 min. Instead of DOTA(tBu)3-OH, AcPCTA(tBu)3-OH (0.1 mmol, 2 eq.) was employed in an overnight reaction with DIPEA (0.2 mmol, 4 eq.), and HATU (0.1 mmol, 2 eq.) in DMF (1 ml), to which A,A'-di isopropylcarbodi imide (0.64 mmol, 12.8 eq.) was added 90 min after start of the reaction. This reaction was repeated and that time performed at 50°C. After 24 h, A,A'-di isopropylcarbodi imide (0.1 mmol, 2 eq.) and Oxyma Pure (0.1 mmol, 2 eq.) were added and the reaction was allowed to proceed for 4 more days at RT.

♦ The reaction with quisqualic acid of the O-succinimidyl carbamate was performed in the presence of 2.5 eq. of DIPEA.

♦ PSM-06 was purified by preparative HPEC using a gradient from 15% B to 35% B in 20 min at a flow rate of 40 ml/min. PSM-06. White solid. Yield: 6.59 mg (5.8 pmol, 12 % of theory, based on Alloc-Lys(Fmoc)-OH- loaded resin). HPEC: Rt = 5.3 min. EC/TOF-MS (m/z for [M+H] ⁺ ): found 1134.474 (calculated 1134.474). C52H67N11O18 (MW = 1134.153).

Example 6: Synthesis of PSM-07 (Formula 27)

Formula 27

Compound PSM-07 was obtained by reacting the activated chelator (PSC-NHS ester) with the chelator-free precursor amine in solution. Synthesis of the chelator-free precursor was performed according to the synthetic procedure as described for PSM-01 in Example 2, with the following alterations:

♦ The synthesis started from Wang resin loaded with 500 pmol Alloc-L-Eys(Fmoc)-OH and scaled up accordingly.

♦ Instead of A-Fmoc-tranexamic acid, A-Boc-tranexamic acid was employed in the chain assembly and coupling of DOTA(tBu)3-OH was omitted.

♦ The Alloc deprotection was performed with the five-fold volume of reagents.

♦ For urea synthesis, two times 50 pmol of resin were employed. The reaction with quisqualic acid of the O-succinimidyl carbamate was performed in the presence of 2.5 eq. of DIPEA and repeated once. ♦ Cleavage from the resin and final deprotection was performed for 2 h instead of 4 h.

♦ The precursor amine was purified by preparative HPLC using a gradient from 10% B to 30% B in 30 min at a flow rate of 40 ml/min. The precursor amine was isolated as a white solid. Yield: 16.40 mg (23.5 pmol, 24 % of theory, based on Alloc-Lys(Fmoc)-OH-loaded resin). HPLC: Rt = 5.0 min. LC/TOF-MS (m/z for [M+H] ⁺ ): found 698.314 (calculated 698.314). C33H43N7O10 (MW = 697.737).

Conjugation of PSC-NHS ester to the precursor amine in solution:

To a stirring solution of the precursor amine (15.0 mg, 21.5 pmol, 1 eq.) in DMSO (0.2 ml) was added 10 pl DIPEA to adjust the pH to ~8. PSC-NHS ester (32 mg, 64.5 pmol, 3 eq.) was added in two portions followed by pH adjustments to ~8 by DIPEA additions. After completion of the reaction as judged by LC-MS, the mixture was subjected to preparative HPLC purification using a gradient from 10% B to 30% B in 20 min at a flow rate of 40 ml/min.

PSM-07. White solid. Yield: 8.52 mg (7.9 pmol, 37 % of theory, based on the purified precursor amine). HPLC: Rt = 4.9 min. LC/TOF-MS (m/z for [M+H] ⁺ ): found 1083.509 (calculated 1083.511). C49H70N12O16 (MW = 1083.153).

Example 7: Synthesis of PSM-08 (Formula 28)

Formula 28

Compound PSM-08 was obtained by reacting the activated chelator with the chelator-free precursor amine in solution. Synthesis of the chelator-free precursor was performed as described in Example 6.

Conjugation of DOTAM-OH to the precursor amine in solution:

To a stirring solution of the precursor amine (15.0 mg, 21.5 pmol, 1 eq.) in DMSO (0.2 ml) was added 15 pl DIPEA to adjust the pH to ~8. To DOTAM-OH (17.3 mg, 43.0 pmol, 2 eq.) in DMSO (0.2 ml) was added HATU (16.4 mg, 43.0 pmol, 2 eq.) and DIPEA (15 pl, 86.0 pmol, 4 eq.) and the pre-activation reaction was allowed to proceed for 2 min and then transferred to the precursor amine. After completion of the reaction as judged by LC-MS, the mixture was subjected to preparative HPLC purification using a gradient from 10% B to 30% B in 20 min at a flow rate of 40 ml/min.

PSM-08. White solid. Yield: 7.27 mg (6.7 pmol, 31 % of theory, based on the purified precursor amine). HPLC: Rt = 4.5 min. LC/TOF-MS (m/z for [M+H] ⁺ ): found 1081.542 (calculated 1081.543). C49H72N14O14 (MW = 1081.183). Example 8: FCM Binding Assay

In order to determine binding of compounds according to the present disclosure to PSMA- expressing cells, a FCM binding assay was established.

PSMA-expressing LNCaP cells (ATCC, Cat.No. CRL-1740) were cultured in RPMI (Sigma- Aldrich, Cat.No. R0883) including 10% fetal calf serum (Biochrom), 2 mM L-glutamine (Sigma- Aldrich, Cat.No. G7513), 1 rnM sodium pyruvate (Sigma-Aldrich, Cat.No. S8636), 100 U/ml penicillin and 100 pg/mL streptomycin (Sigma, Cat. No.P0781) and 1 nM R1881 (Sigma-Aldrich, Cat.No. R0908). Cells were detached with Accutase (Biolegend, Cat.No. BLD-423201) and washed in FCM buffer (PBS (Sigma, Cat.No. D8537) including 1% fetal calf serum). Cells were diluted in FCM buffer to a final concentration of 500.000 cells per ml. 200 pL of the cell suspension were transferred to a u-shaped non-binding 96-well plate (Greiner Bio-One, Cat.No. 650901) and cells were washed in ice-cold FCM buffer.

For IC50 determination, cells were incubated with 8 nM 3BP-2354 (Formula 37) which binds to PSMA, which corresponds to the ECso of 3BP-2354, in the presence of increasing concentrations of test compounds at 4°C for 1 hour. After two wash steps with ice-cold FCM buffer, cells were incubated with 1 pg/mL APC-Streptavidin (Miltenyi, Cat.No. 130-106-791) in 50 pL FCM buffer for 30 minutes on ice followed by two additional wash steps with FCM buffer.

Formula 37

Synthesis of 3BP-2354 (Formula 37)

For preparation of 3BP-2354, a solid phase synthesis was performed on trityl resin manually loaded with Fmoc-Lys(Alloc)-OH. The order of synthetic steps was 1. urea synthesis on the a amine of the lysine, 2. deprotection of the alloc group on the s amine of the lysine, and 3. automated solid phase synthesis to assemble the polyamide chain on the s amine of the lysine.

Manual resin loading:

The resin (2-chlorotrityl chloride resin, 2.0 g, 3.1 mmol, 1 eq, initial loading: 1.55 mmol/g) was swollen in DCM/DMF (1: 1, v/v, 25 ml) for 30 minutes and subsequently washed with DCM/DMF (1: 1, v/v, 25 ml, 1 minute). Then the resin was treated with a mixture of Fmoc-Lys(Alloc)-OH (4.65 mmol, 2.1 g, 1.5 eq.) and DIPEA (2.4 ml, 13.5 mmol, 4.4 eq.) in DCM/DMF (25 ml) for 90 minutes. Afterwards the resin was washed with methanol (25 ml, 10 minutes) and DMF (25 ml, 2x 1 minute). Resin loading was 0.35 mmol/g as determined by cleaving the Fmoc group from the resin bound Fmoc-Lys(Alloc)-OH with piperidine and photometerical determination of the resulting dibenzofulvene-piperidine adduct.

Urea synthesis: To a stirring mixture of L-glutamic acid di-tert-butyl ester hydrochloride (2.5 g, 8.5 mmol, 10 eq.) and triphosgene (0.83 g, 2.8 mmol, 3.3 eq.) in dry DCM (28 ml) at -20°C was added dropwise DIPEA (5.8 ml, 34 mmol, 40 eq.). After one hour, the reaction was allowed to warm to 0°C. Meanwhile, the Lys(Alloc)-loaded trityl resin (0.85 mmol, 1 eq.) was swollen in dry DCM (25 ml) for 30 minutes and subsequently washed with dry DCM (25 ml, 3x1 minute). The reaction mixture was then transferred to the resin and agitated at RT overnight. After draining, the resin was washed with DCM (25 ml, 3 x 1 minute), and dried in vacuo.

Alloc deprotection:

Alloc deprotection was performed as described for the synthesis of PSM-01.

Automated solid phase synthesis:

Automated solid phase synthesis was performed at a 100 pmol scale, essentially as described for the synthesis of PSM-01 using a ratio of building block/HATU/DIPEA of 5 eq./5 eq./lO eq. The used building blocks were A-Fmoc-3-(2-naphthyl)-L-alanine, A-Fmoc-tranexamic acid, Fmoc- Ttds-OH, and biotin in this order.

Cleavage from solid phase and final deprotection were performed as described for PSM-01. 3BP- 2354 was purified accordingly by preparative HPEC using a linear gradient from 15% B (and correspondingly 85% A) to 40% B (and correspondingly 60% A) in 30 min at a flow rate of 30 ml/min. Fractions containing the pure product were pooled and freeze dried.

3BP-2354. White solid. Yield: 53.2 mg (45.0 pmol, 45 % of theory, based on Fmoc-Eys(Alloc)- OH-loaded resin). HPEC: R _t = 5.8 min. EC/TOF-MS (m/z for [M+H] ⁺ ): found 1184.592 (calculated 1184.593). C57H ₈₅ N ₉ Oi6S (MW = 1184.404).

Cells were analyzed using an Attune NxT flow cytometer. Median fluorescence intensities (MFI) of the APC-channel were calculated by Attune NxT software. MFI values were plotted against peptide concentration and four parameter logistic (4PE) curve fitting and pICso calculations were performed using ActivityBase software (IDBS).

The results of the pICso assay are shown in Table 5. Table 5: Compound ID, pICso ± SD according to FCM binding assay

Example 9: Surface Plasmon Resonance Assay

Surface plasmon resonance (SPR) studies were performed using a Biacore™ T200 SPR system. Briefly, polarized light is directed towards a gold-labeled sensor surface, and minimum intensity reflected light is detected. The angle of reflected light changes as molecules bind and dissociate.

Fc-fusion protein of human PSMA (hPSMA-Fc, Aero Biosystems, #PSA-H5264, Lot 3504b- 203EF1-SJ) was captured on a Fc-capture chip (Biacore™ CM5 sensor chip coated with -400 RU of an Fc-binding peptide). hPSMA-Fc was diluted in Running Buffer (HBST from Xantec Analytics; 150 nM NaCl, 0.05% Tween20, 0.1% DMSO) to a final concentration 100 nM and then flushed over the Fc-capture chip to immobilized -3000 RUs.

Stock solutions of test compounds were prepared by dissolving each compound in DMSO. DMSO stock solution were diluted 1 : 1000 in Running Buffer without DMSO. Further sequential dilutions were made with Running Buffer containing 0.1% DMSO. SPR binding analyses were performed in Single Cycle Kinetic (SCK) mode at 25°C. Flow cell coated with the Fc-binding peptide only served as reference flowcell. After each SCK run, PSMA-Fc was removed with 6 M Guanidine - HC1 . In between every three SCK measurements, a blank run with Running Buffer instead of test compound was included to correct for baseline drifts (double blanking method).

Table 6 describes the protocol steps for Fc-fusion target capturing and assessment of the binding kinetics.

Table 6: SPR protocol steps with hPSMA-Fc immobilization.

For each test compound, SPR raw data in the form of resonance units (RU) were plotted as sensorgrams using the Biacore™ T200 control software. The signal from the blank sensorgram was subtracted from that of the test compound sensorgram (blank corrected). The blank corrected sensorgram was corrected for baseline drift by subtracting the sensorgram of a SCK run without the test compound (running buffer only). The association rate (k _on ), dissociation rate (k _O ff), dissociation constant (KD), and ti/2 (half-life) were calculated from blank corrected SPR data using the 1:1 Langmuir binding model from the Biacore™ T200 evaluation software. Raw data and fit results were imported as text files in ActivityBase (IDBS). The pKo value (negative decadic logarithm of dissociation constant) was calculated in the ActivityBase. Figure 2 shows a representative sensorgram for compound PSM-01. The results of this assay for a selection of representative compounds according to the present disclosure are presented in Table 7.

Table 7: Compound ID, pKo value according to SPR assay.

For PSM-08, a pKn value of greater than 9 was estimated.

Example 10: ¹¹¹ In-labeling

In order to serve as a diagnostically, therapeutically, or theragnostically active agent, a compound according to the present disclosure may be labeled with a radioactive isotope. The labeling procedure needs to be appropriate to ensure a high radiochemical yield and purity of the radiolabeled compound of the disclosure. This example shows that the compounds of the present disclosure are appropriate for radiolabeling and can be labeled in high radiochemical yield and purity.

49 - 102 MBq of ⁱⁿ InC13 (in 0.02 M HC1; Curium, Germany) were mixed with 1 nmol of compound PSM-01 (500 pM stock solution in ultrapure water) per 30 MBq and buffer (I M sodium acetate pH 5) at a final buffer concentration of 0.1 M. The mixture was heated to 80 °C for 25 min. After cooling down, ascorbic acid (Woerwag Pharma, Germany), DTPA (Heyl, Germany) and TWEEN-20 were added at a final concentration of 25 mg/mL, 0.1 mg/mL and 0.1%, respectively.

Radiochemical purity was analyzed by HPLC. 5 pl of diluted labeling solution was analyzed with a Poroshell SB-C18 2.7 pm, 2.1 x 50 mm (Agilent). Eluent A: H2O, 0.1 % TFA eluent B: MeCN, gradient from 5% B to 70% B within 15 min, flow rate 0.5 mL/min; detector: Nal (Raytest), DAD 230 nm. The peak eluting with the dead volume represents free radionuclide, the peak eluting with the compound-specific retention time as determined with an unlabeled sample (R _t = 6.24 min) represents radiolabeled compound (R _t = 6.00 min).

Radiochemical purity was > 90% at end of synthesis. An exemplary radiochromatogram of ^{1 1 1} Inlabelled PSM-01 (Formula 29) is shown in Figure 3 with all peaks labeled with their retention times.

Example 11: Imaging and biodistribution studies

Radioactively labeled compounds can be detected by imaging methods such as SPECT and PET. Furthermore, the data acquired by such techniques can be confirmed by direct measurement of radioactivity contained in the individual organs prepared from an animal injected with a radioactively labeled compound of the disclosure. Thus, the biodistribution (the measurement of radioactivity in individual organs) of a radioactively labeled compound can be determined and analyzed. This example shows that the compounds of the present disclosure show a biodistribution appropriate for diagnostic imaging and therapeutic treatment of tumors.

All animal experiments were conducted in compliance with the German animal protection laws. Male swiss nude mice (7 weeks old, Charles River Laboratories, France) were inoculated with IxlO ⁷ LNCaP cells in the right and 5xl0 ⁶ PC-3-PSMA (human prostate cancer cells genetically engineered to express human PSMA) cells in the left shoulder. When tumors reached an appropriate size, the mice received ~30 MBq ¹¹¹ In-labelled PSM-01 of the disclosure (diluted to 100 p with PBS) administered intravenously via the tail vein. Images were obtained on a NanoSPECT/CT system (Mediso Medical Imaging Systems, Budapest, Hungary) using exemplarily the following acquisition and reconstruction parameters (Table 8).

Table 8 : Acquisition and reconstruction parameters of NanoSPECT/CT imaging

Imaging data were saved as DICOM files and analysed using VivoQuant™ software (Invicro, Boston, USA). Two animals were used per time point. Results are expressed as a percentage of injected dose per gram of tissue (%ID/g).

The results of the imaging are shown in Figure 4 and Figure 5. Figure 4 shows the percentage of injected dose per gram of tissue uptake (mean %ID/g, error bars indicate standard deviation) in the kidneys, liver, bloodpool and ENCaP as well as PC-3-PSMA tumors as determined by SPECT/CT imaging of ⁱⁿ In-PSM-01 1 h, 4 h, and 24 h post injection into the mouse model. Figure 5 shows an exemplary SPECT image of ⁿⁱ In-PSM-01 24 h post injection into one mouse with LNCaP and PC-3-PSMA tumors. Example 12: Plasma stability assay

In order to determine the stability of selected compounds of the disclosure in human and mouse plasma, a plasma stability assay was carried out. Such plasma stability assay measures degradation of compounds of the present disclosure in blood plasma. This is an important characteristic of a compound, as compounds, with the exception of pro-drugs, which rapidly degrade in plasma, generally show poor in vivo efficacy. The results show that those compounds are highly stable in human and mouse plasma. The stability is sufficient for the diagnostic, therapeutic and theragnostic use of these compounds according to the present disclosure.

The plasma stability samples were prepared by spiking 50 pl plasma aliquots (all sodium citrate) with 1 pl of a 0.5 mM compound stock solution in DMSO. After vortexing the samples were incubated in a Thermomixer at 37 °C for 0, 2 6 and 24 hours. After incubation the samples were stored on ice until further treatment. All samples were prepared in duplicates.

A suitable internal standard was added to each sample (1 pl of a 0.5 mM stock solution in DMSO). Protein precipitation was performed by addition of 200 pL ethanol followed by incubation on ice for 60 min. The precipitate was separated by centrifugation and 150 pl of the supernatant was diluted with 150 pl of 1% aqueous formic acid.

The determination of the analyte in the clean sample solutions was performed on an Agilent 1290 UHPLC system coupled to an Agilent 6530 Q-TOF mass spectrometer. The chromatographic separation was carried out on a Phenomenex BioZen XB-C18 HPLC column (50 x 2 mm, 1.7 pm particle size) with gradient elution using a mixture of 0.1% formic acid in water as eluent A and acetonitrile as eluent B (2% B to 41% in 7 min, 800 pl/min, 40°C). Mass spectrometric detection was performed in positive ion ESI mode by scanning the mass range from m/z 50 to 3000 with a sampling rate of 2 / sec.

From the mass spectrometric raw data the ion currents for the double charged monoisotopic signal was extracted for both, the compound and the internal standard. Quantitation was performed by external matrix calibration with internal standard using the integrated analyte signals.

Additionally, recovery was determined by spiking a pure plasma sample that only contained the internal standard after treatment with a certain amount of the compound.

Carry-over was evaluated by analysis of a blank sample (20% acetonitrile) after the highest calibration sample.

The results of the mouse stability assay performed on PSM-01 are given in the following Table 9. The result is stated as “% intact compound remaining” and means that from the amount of material at the start of the experiment the stated percentage is detected as unchanged material at the end of the experiment by LC-MS quantification. Since the compounds showed no degradation after 24 hours incubation, it is considered that the stability is sufficient for diagnostic, therapeutic, and theragnostic applications.

Table 9: Results of the plasma stability assay for PSM-01

Example 13: Imaging study using ⁶⁸ Ga-labeled PSM-01 (Formula 30)

In order to evaluate the tumor binding characteristics of radiolabelled compound ⁶⁸ Ga-labeled PSM-01 (Formula 30) in patients, an imaging study is carried out. Such an imaging study may serve to characterize, for example, the comparative tumor binding properties of ⁶⁸ Ga-labeled PSM- 01 (Formula 30) relative to ⁶⁸ Ga-PSMA-l l, as well as to determine binding characteristics of compounds in non-tumor organs. Patients in the study are those who are undergoing or have completed treatment for metastatic castration resistant prostate cancer (mCRPC) with biochemical or radiographic disease progression. Disease progression is demonstrated by a PSA increase of > 2ng/dL from the most recent nadir or by traditional imaging, such as, CT, MRI, or bone scan. Up to 10 patients are enrolled.

⁶⁸ Ga-Labeling ( ⁶⁸ Ga-PSM-01): Radiolabeling can be performed, for example, upon reacting gallium-68 and the compound PSM-01 under acidic conditions (pH 4.0 - 5.5) at 80 - 95°C for 10 - 30 min. The reaction can be purified using, e.g., solid phase extraction.

⁶⁸ Ga-labeled PSM-01 (Formula 30) is administered intravenously as a single dose (e.g., 1 mCi to 10 mCi, or 3 mCi to 7 mCi) to patients on Day 1 of the study. Imaging of ⁶⁸ Ga-labeled PSM-01 is performed on a PET/CT system at 1 h and 4 h post administration.

⁶⁸ Ga-Labeling ( ⁶⁸ Ga-PSMA-l l): Radiolabeling can be performed, for example, upon reacting gallium-68 and the compound PSMA-11 under acidic conditions (pH 4.0 - 4.5) at 25 - 95 °C for 10 - 20 min. The reaction can be purified using, e.g., solid phase extraction.

⁶⁸ Ga-PSMA-l l is administered intravenously as a single dose (e.g., 1 mCi to 10 mCi, or 3 mCi to 7 mCi) to the same patients on one of Days 3-8. Imaging of ⁶⁸ Ga-PSMA-l 1 is performed on a PET/CT system at 1 h and 4 h post administration.

⁶⁸ Ga-PSMA-l l

A study objective includes characterizing the tumor binding properties of ⁶⁸ Ga-labeled PSM-01 as compared to ⁶⁸ Ga-PSMA-l l, in patients with mCRPC by comparing the respective maximum standardized uptake values (SUVmax) and/or SUV mean and/or total tumor volume obtained by PET/CT imaging. Another study objective includes characterizing the binding properties of ⁶⁸ Ga- labeled PSM-01 in normal or non-tumor tissues/organs (e.g., salivary glands, kidneys, small intestine, or other non-tumor tissues/organs).

The results can show binding properties, including, for example, tumor uptake, tumor retention, tumor to non-tumor binding ratios, and clearance from non-tumor tissues, which are appropriate for diagnostic imaging and therapeutic treatment of tumors.

Example 14: Imaging study using ⁶⁸ Ga-labeled PSM-01 (Formula 30)

In order to evaluate the tumor binding characteristics of radiolabelled compound ⁶⁸ Ga-labeled PSM-01 (Formula 30) in patients, an imaging study is carried out. Such an imaging study may serve to characterize, for example, the comparative tumor binding properties of ⁶⁸ Ga-labeled PSM- 01 (Formula 30) relative to ⁶⁸ Ga-PSMA I&T, as well as to determine binding characteristics of compounds in non-tumor organs. Patients in the study are those who are undergoing or have completed treatment for metastatic castration resistant prostate cancer (mCRPC) with biochemical or radiographic disease progression. Disease progression is demonstrated by a PSA increase of > 2ng/dE from the most recent nadir or by traditional imaging, such as, CT, MRI, or bone scan. Up to 10 patients are enrolled.

⁶⁸ Ga-labeled PSM-01 (Formula 30) is administered intravenously as a single dose (e.g., 1 mCi to 10 mCi, or 3 mCi to 7 mCi) to patients on Day 1 of the study. Imaging of ⁶⁸ Ga-labeled PSM-01 is performed on a PET/CT system at 1 h and 4 h post administration.

⁶⁸ Ga-Eabeling ( ⁶⁸ Ga-PSMA I&T): Radiolabeling of PSMA I&T can be performed, for example, using a procedure analogous to the radiolabeling procedure for ⁶⁸ Ga-PSM-01 described in Example 13. ⁶⁸ Ga-PSMA I&T is administered intravenously as a single dose (e.g., 1 mCi to 10 mCi, or 3 mCi to 7 mCi) to the same patients on one of Days 3-8. Imaging of ⁶⁸ Ga-PSMA I&T is performed on a PET/CT system at 1 h and 4 h post administration.

⁶⁸ Ga-PSMA I&T

A study objective includes characterizing the tumor binding properties of ⁶⁸ Ga-labeled PSM-01 as compared to ⁶⁸ Ga-PSMA I&T, in patients with mCRPC by comparing the respective maximum standardized uptake values (SUVmax) and/or SUV mean and/or total tumor volume obtained by PET/CT imaging. Another study objective includes characterizing the binding properties of ⁶⁸ Ga- labeled PSM-01 in normal or non-tumor tissues/organs (e.g., salivary glands, kidneys, small intestine, or other non-tumor tissues/organs).

The results can show binding properties, including, for example, tumor uptake, tumor retention, tumor to non-tumor binding ratios, and clearance from non-tumor tissues, which are appropriate for diagnostic imaging and therapeutic treatment of tumors.

References

The disclosure of each and any document recited herein is incorporated by reference.