FIELD OF THE INVENTION

[0001 ] The present invention relates to the field of medical imaging. More particularly, the invention relates to imaging agents and the production thereof.

BACKGROUND TO THE INVENTION

[0002] Any reference to background art herein is not to be construed as an admission that such art constitutes common general knowledge in Australia or elsewhere.

[0003] Positron emission tomography (PET) is a useful imaging technique that can produce three-dimensional images of processes in the body. PET measures the physiological function by observing blood flow, metabolism, neurotransmitters and radiolabeled agents. This technique is based on the indirect detection of gamma rays and radiation emitted by a radioactive agent that is injected into the body.

[0004] The radioactive agent, which has a radionuclide, is injected into the body where it undergoes positron emission decay to emit a positron which then collides with an electron in the tissue to form two photons. A PET camera then detects these protons in the form of light which is converted into an electrical signal to give an image which can be observed by an appropriate medical professional.

[0005] As previously mentioned, PET imaging can probe blood flow and oxygen consumption, and this is useful in oncology because tumour growths tend to be hypoxic because they are deprived of oxygen due to their rapid growth. These regions therefore have significantly lower blood flow which can be observed. [0006] Radionuclides that are used in PET scanning are typically isotopes with short half-lives, and as such these PET imaging agents must be prepared and used shortly after preparation to detect the resultant decay. The short half- life also means that these imaging agents cannot be stored in the form in which they are administered.

[0007] In brain imaging it is essential that the imaging agent must be able to cross the blood-brain barrier (BBB). This requires low molecular mass, a neutral charge and moderate lipophilicity. The imaging agent should be sufficiently lipophilic to cross the BBB, but also not so lipophilic that it will bind to proteins to an undesirable extent which can in itself prevent crossing of the BBB.

[0008] Inorganic labelling of a molecule with ¹⁸ F has been described in WO 2009/079024, which discloses a method of reacting a ¹⁸ F atom with a metal to form a ¹⁸ F metal complex that can be administered to a patient. Further to this, WO 201 1/068965 discloses a method of labelling a molecule with ¹⁸ F or ¹⁹ F comprising the steps of attaching a complex of ¹⁸ F or ¹⁹ F and a group IMA metal to a chelating moiety, wherein the chelating moiety is conjugated to a targeting molecule or the chelating moiety is later attached to the targeting molecule. This patent also discloses that aluminium, gallium, indium, and thallium are suitable for fluorine binding. [0009] The prior art methods of WO 2009/07902 and WO 201 1/068965 do, however, have some limitations. In particular, the metal-fluorine complexes formed from the ligands used are hydrophilic and the imaging agents generated from these methods will be less effective at crossing the BBB.

[0010] Therefore, there is a need for alternative metal-fluorine based imaging agents that show one or more of the following advantages: are lipophilic, that can be produced safely and easily in real time, administered quickly after production, readily cross the blood-brain barrier, and may utilize a number of different radionuclides. SUMMARY OF THE INVENTION

[001 1 ] In a first aspect, although it need not be the only or indeed the broadest aspect, the invention resides in a compound of formula (I)

Formula (I) wherein,

Ri and R ₂ are independently selected from the group consisting of hydrogen, hydroxyl, amine, amide, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C12 alkoxy, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;

R ₃ , R ₄ , R ₅ , R ₆ are independently selected from the group consisting of hydrogen, hydroxyl, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;

Ei and E ₂ are independently selected from S, O, or Se; F is ¹⁸ F or ¹⁹ F; and

M is a transition metal ion, or a radioisotope thereof.

[0012] In an embodiment, Ri and R ₂ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1 -C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1 -C6 alkoxy, substituted or unsubstituted C1 -C6 acyl, substituted or unsubstituted C3- C6 cycloalkyl, and substituted or unsubstituted C1 -C6 haloalkyl.

[0013] In one embodiment, Ri and R ₂ are independently selected from hydrogen, substituted or unsubstituted C1 -C6 alkyl, and substituted or unsubstituted aryl.

[0014] In another embodiment, Ri and R ₂ are independently selected from hydrogen, methyl, ethyl, or phenyl.

[0015] In one embodiment, M is a transition metal ion with an oxidation state of +3.

[0016] In an embodiment, wherein M is a transition metal ion with an oxidation state of +3, then it may be selected from the group consisting of Al ³⁺ , Ga ³⁺ , ln ³⁺ , Sc ³⁺ , Y ³⁺ , Ho ³⁺ , Tm ³⁺ , Yb ³⁺ , and Lu ³⁺ .

[0017] In one embodiment, M is Al ³⁺ , Ga ³⁺ or ln ³⁺ . [0018] In another embodiment, wherein M is a radioisotope of a transition metal, then it may be selected from the group consisting of radioisotopes of gallium, and indium.

[0019] In one embodiment, wherein M is a radioisotope of a transition metal, then it may be selected from the group consisting of ⁶⁷ Ga, ⁶⁸ Ga and ¹¹¹ In. [0020] In one embodiment, at least one of M or F will be a radionuclide. Put another way, if F is ¹⁹ F then M is a transition metal radionuclide.

[0021 ] It is preferred that only one of M and F is a radionuclide.

[0022] In one embodiment, Ei and E ₂ are independently selected from S and O. [0023] In one particular embodiment, Ei and E ₂ are S.

[0024] In an embodiment R ₃ , R ₄ , R ₅ and R ₆ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1 -C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1 -C6 alkoxy, substituted or unsubstituted C1 -C6 acyl, substituted or unsubstituted C3- C6 cycloalkyl, and substituted or unsubstituted C1 -C6 haloalkyl.

[0025] In one embodiment R ₃ , R ₄ , R ₅ and R ₆ are independently selected from hydrogen and substituted or unsubstituted C1 -C6 alkyl.

[0026] In certain embodiments, R ₃ , R ₄ , R ₅ and R ₆ are H.

[0027] In one particular embodiment, when Ri is hydrogen then R ₂ may not be hydrogen.

[0028] In a second aspect, the invention resides in an imaging complex comprising a compound of formula (I) linked to a biomarker:

wherein

l_n is a linker group;

n is 0 or 1 ; and

BM is a biomarker.

[0029] The compound of formula (I) may be substantially as described in any one or more embodiments of the first aspect. [0030] In a third aspect, the invention resides in a method of preparing a compound of formula (I) comprising the steps of: a. providing a compound of formula (II):

wherein,

Ri and R ₂ are independently selected from the group consisting of hydrogen, hydroxyl, amine, amide, halogen, PEG, N-PEG substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C12 alkoxy, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;

R ₃ , R ₄ , R ₅ , R ₆ are independently selected from the group consisting of hydrogen, hydroxyl, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C8 acryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;

Ei and E ₂ are independently selected from S, O, or Se;

M is a transition metal ion, or a radioisotope thereof; X is a leaving group; and b. substituting X with ¹⁸ F or ¹⁹ F.

[0031 ] Ri , R ₂ , R3, R , R5, Re, Ei , E ₂ and M may independently be as substantially described in any one or more embodiments of the first aspect.

[0032] In one embodiment, the leaving group X is selected from the group consisting of chloride, bromide, iodide, nitrate, acetate, citrate, sulfonate, and triflate.

[0033] In one particular embodiment, the leaving group X is a nitrate group.

[0034] In one embodiment, when X is substituted with ¹⁹ F then M is a transition metal radionuclide.

[0035] In one embodiment, step b. comprises treating the compound of formula (II) with an appropriate fluorine salt.

[0036] In a fourth aspect, the invention resides in a method of medical imaging of a patient comprising the steps of: a. administering a compound of formula (I) to the patient

Formula (I) wherein,

Ri and R ₂ are independently selected from the group consisting of hydrogen, hydroxyl, amine, amide, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C12 alkoxy, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl, ;

R ₃ , R ₄ , R ₅ , R ₆ are independently selected from the group consisting of hydrogen, hydroxyl, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;

Ei and E ₂ are independently selected from S, 0, or Se;

F is ¹⁸ F or ¹⁹ F;

M is a transition metal ion, or a radioisotope thereof; and b. detecting the radioactive decay from the ¹⁸ F or the transition metal radioisotope.

[0037] The compound of formula (I) may be substantially as described in any one or more embodiments of the first aspect.

[0038] In one embodiment, the medical imaging is PET imaging.

[0039] In another embodiment, the medical imaging is SPECT imaging. [0040] The various features and embodiments of the present invention referred to in the individual sections above apply, as appropriate, to other sections, mutatis mutandis. Consequently features specified in one section may be combined with features specified in other sections as appropriate.

[0041 ] Further features and advantages of the present invention will become apparent from the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order that the invention may be readily understood and put into practical effect, preferred embodiments will now be described by way of example with reference to the accompanying figures wherein:

FIG 1 shows a graphical representation of a time activity curve for a first mouse injected with ¹⁸ F thiosemicarbazone;

FIG 2 shows a graphical representation of a time activity curve for a second mouse injected with ¹⁸ F thiosemicarbazone;

FIG 3 shows an X-ray structure of the diphenylthiosemicarbazone gallium chloride complex; and

FIG 4 shows an X-ray structure of the diphenyl thiosemicarbazone gallium methoxide complex.

DETAILED DESCRIPTION OF THE INVENTION

[0043] Embodiments of the present invention reside primarily in imaging agents. Accordingly, the method steps have been illustrated in concise schematic form describing those specific details that are necessary to understanding the embodiments of the present invention, but so as not to obscure the disclosure with excessive detail that will be readily apparent to those of ordinary skill in the art having the benefit of the present description.

Definitions

[0044] In this patent specification, the terms 'comprises', 'comprising', 'includes', 'including', or similar terms are intended to mean a non-exclusive inclusion, such that a method or groups that comprises a list of elements does not include those elements solely, but may well include other elements not expressly listed.

[0045] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as would be commonly understood by those of ordinary skill in the art to which this invention belongs.

[0046] The term "substituted" in each incidence of its use herein, and in the absence of an explicit listing for any particular moiety, refers to substitution of the relevant moiety, for example an alkyl chain or ring structure, with one or more more groups selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, CN, OH, oxo, NH ₂ , CI, F, Br, I, aryl and heterocyclyl which latter two may themselves be optionally substituted.

[0047] The term "alkyf refers to a straight-chain or branched alkyl substituent containing from, for example, 1 to about 12 carbon atoms, preferably 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms, even more preferably from 1 to about 4 carbon atoms, still yet more preferably from 1 to 2 carbon atoms. Examples of such substituents include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, terf-butyl, pentyl, isoamyl, 2-methylbutyl, 3- methylbutyl, hexyl, heptyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2- ethylbutyl, 3-ethylbutyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The number of carbons referred to relate to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents, for example the carbon atoms of an alkoxy substituent branching off the main carbon chain.

[0048] The term "cycloalkyl" refers to optionally substituted saturated monocyclic, bicyclic or tricyclic carbon groups. Where appropriate, the cycloalkyl group may have a specified number of carbon atoms, for example, C3-C6 cycloalkyl is a carbocydic group having 3, 4, 5 or 6 carbon atoms. Non-limiting examples may include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like.

[0049] The term "alkoxy" refers to an unsubstituted or substituted alkyl group linked by an oxygen atom (i.e., -O-Alkyl), wherein alkyl is described above. In particular embodiments, alkoxy refers to oxygen-linked groups comprising 1 to 12 carbon atoms ("C1 -C12 alkoxy"). In further embodiments, alkoxy refers to oxygen-linked groups comprising 1 to 8 carbon atoms ("C1 -8 alkoxy"), 1 to 6 carbon atoms ("C1 -6 alkoxy"), 1 to 4 carbon atoms ("C1 -4 alkoxy"), 1 to 3 carbon atoms ("C1 -3 alkoxy"), or 1 to 2 carbon atoms ("C1 -2 alkoxy").

[0050] The term "aryl" refers to an unsubstituted or substituted aromatic carbocydic substituent, as commonly understood in the art. It is understood that the term aryl applies to cyclic substituents that are planar and comprise 4n+2 π electrons, according to Huckel's Rule. C-5 or C-6 aryl is preferred.

[0051 ] The terms "heterocyclic" and "heterocyclyl" as used herein refer to a non-aromatic ring having 5 to 7 atoms in the ring and of those atoms 1 to 4 are heteroatoms, said ring being isolated or fused to a second ring wherein said heteroatoms are independently selected from O, N and S. Heterocyclic includes partially and fully saturated heterocyclic groups. Heterocyclic systems may be attached to another moiety via any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated. Non-limiting examples of heterocyclic may be selected from pyrazole, imidazole, indole, isoindole, triazole, benzotriazole, tetrazole, pyrimidine, pyridine, pyrazine, diazine, triazine, tetrazine, pyrrolidinyl, pyrrolinyl, pyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, dithiolyl, oxathiolyl, dioxanyl, dioxinyl, oxazinyl, azepinyl, diazepinyl, thiazepinyl, oxepinyl and thiapinyl, imidazolinyl, thiomorpholinyl, and the like. C-5 or C-6 heterocycles are preferred.

[0052] Whenever a range of the number of atoms in a structure is indicated (e.g., a C1-C12, C-i-do, C1-C9, C1-C6, C1-C4, alkyl, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1 -12 carbon atoms (e.g., C1-C12), 1 -9 carbon atoms (e.g., C1-C9), 1 -6 carbon atoms (e.g., C-i-Ce), 1 -4 carbon atoms (e.g., C1-C4), 1 -3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C2-C8) as used with respect to any chemical group (e.g. , alkyl, etc.) referenced herein encompasses and specifically describes 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , and/or 12 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1 -2 carbon atoms, 1 -3 carbon atoms, 1 -4 carbon atoms, 1 -5 carbon atoms, 1 -6 carbon atoms, 1 -7 carbon atoms, 1 -8 carbon atoms, 1 -9 carbon atoms, 1 -10 carbon atoms, 1 -1 1 carbon atoms, 1 -12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-1 1 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-1 1 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-1 1 carbon atoms, and/or 4-12 carbon atoms, etc., as appropriate).

[0053] As used herein, the terms "subject" or "individual" or "patient" may refer to any subject, particularly a vertebrate subject, and even more particularly a mammalian subject, for whom diagnosis via medical imaging is desired. Suitable vertebrate animals include, but are not restricted to, primates, avians, livestock animals (e.g., sheep, cows, horses, donkeys, pigs), laboratory test animals (e.g. , rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g., cats, dogs) and captive wild animals (e.g., foxes, deer, dingoes). A preferred subject is a human in need of diagnosis for a disease or condition.

[0054] In this specification, the indefinite articles "a" and "an" may refer to one entity or a plurality of entities (e.g. components) and are not to be read of understood as being limited to a single entity.

[0055] In a first aspect, although it need not be the only or indeed the broadest aspect, the invention resides in a compound of formula (I)

wherein

Ri and R ₂ are independently selected from the group consisting of hydrogen, hydroxyl, amine, amide, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C12 alkoxy, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;

R ₃ , R ₄ , R ₅ , R ₆ are independently selected from the group consisting of hydrogen, hydroxyl, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl; Ei and E ₂ are independently selected from S, 0, or Se;

F is ¹⁸ F or ¹⁹ F; and

M is a transition metal ion, or a radioisotope thereof.

[0056] A typical prior art imaging agent utilizes ^99m Tc due to its half-life of 6.02 hours. However, there is a shortage of ⁹⁹ Mo, the parent isotope of ^99m Tc and so many have turned to other radionuclides for their imaging agents. The inventors postulate that the compounds of formula (I) can be used to efficiently cross the blood-brain barrier (BBB) and this is particularly useful in PET and SPECT imaging. The BBB allows passage of water, some gases and lipid- soluble molecules by passive diffusion, as well as selective transport of molecules. A person skilled in the art will understand that the compounds of formula (I) can be modified to change the lipophilic profile, and hence lipid- solubility, of the compound to allow for efficient transport across the BBB. These compounds may also alleviate the problems associated with loss of efficacy during the time taken for the imaging agent to cross the BBB. [0057] The compounds of formula (I) allow for the possibility of different radionuclides to be used. In one embodiment, the radionuclide can be present in the form of the ¹⁸ F radionuclide of fluorine. In an alternative embodiment, the compound of formula (I) may comprise a radionuclide in the form of a radioactive isotope of the transition metal M. Suitable radioactive isotopes of the transition metal ion include ⁶⁷ Ga, ⁶⁸ Ga, and ^{11 1} ln. It will be appreciated by a person skilled in the art that the list of radioactive isotopes provided above is not an exhaustive list, but merely identifies some of the radioactive isotopes that may be utilized.

[0058] It should be clear that the compound of formula (I) can accommodate different radionuclides and therefore alleviate the reliance on any single radionuclide. Further to this, the compounds of formula (I) can be utilized with selected radionuclides tailored to different imaging techniques. For instance, when the metal ion is ⁶⁷ Ga or ¹¹¹ In then the modality would be SPECT.

[0059] The compounds of formula (I) are useful as imaging agents as they are stable, non-toxic, can be easily generated and safely administered. Further to this, the compounds of formula (I) lessen dependence on ^99m Tc. It will also be appreciated by a person skilled in the art that either one of M or F can be the radionuclide, or, alternatively, both M and F can be radionuclides.

[0060] A number of synthetic pathways can be employed to access the compounds of the present invention. Scheme 1 , below, depicts one possible pathway by which a compound of formula (I) can be synthesized.

where R,=H, Mc,Ph; R ₂ =H,Mc,Et,Ph; M = Ga, Al, In

Scheme 1 - A synthetic pathway to a thiosemicarbazone metal ¹⁸ F complex

[0061 ] The compounds of formula (I) can be readily prepared without the need for any specialized equipment. This alleviates the problems associated with short half-life, and allows for radionuclides with shorter half-lives to be used because the compound can be generated in a basic laboratory or suitable preparation room and administered to a patient relatively quickly. Further to this, the preparation is simple and does not require any advanced synthetic knowledge or specialist tools or skills. [0062] It is believed that the molecular weight, log P value and overall charge of a compound of formula (I) are linked with the efficiency of the compound crossing the blood brain barrier. Advantageously, the compounds of formula (I) provide for desirable values in each of these areas of consideration.

[0063] In one embodiment, the compound of formula (I) has a molecular weight suitably less than 1000 daltons, more suitably less than 800 daltons, preferably less than 700 daltons, and most preferably less than 600 daltons. Each of these values may be combined with a lower value selected from 50, 75 or 100 daltons.

[0064] In another embodiment, the compound of formula (I) has a log P value of between about +0.5 and about +2.5.

[0065] In an embodiment, the compound of formula (I) has an overall neutral charge.

[0066] In one embodiment, the compound of formula (I) may be selected from the group consisting of:

metal ion may be ⁶⁷ Ga or ⁶⁸ Ga or may be replaced with ¹¹¹ In. Each such analogue is considered to have been explicitly disclosed herein for each compound structure drawn above.

[0067] In a second aspect, the invention resides in an imaging complex comprising a compound of formula (I) linked to a biomarker:

wherein l_n is a linker group;

n is 0 or 1 ; and

BM is a biomarker. [0068] The compound of formula (I) may be substantially as described in any one or more embodiments of the first aspect.

[0069] The linker group can be any linker group that attaches to the compound of formula (I) to a biomarker. Suitable linker groups include alkyl, amides, ethers, esters, alkenyl, acetyl groups, alkynyl groups, PEG, N-PEG, and amino acids. It will appreciated by a person skilled in the art that that the list provided is not an exhaustive list of linker groups, but merely demonstrate the types of linker groups that can be used to link the compound of formula (I) to a biomarker.

[0070] The biomarker can suitably be a naturally occurring molecule or gene which is capable of identifying a pathological or physiological process or disease.

[0071 ] The biomarker may be a compound comprised of moieties that recognize, bind or adhere to a target moiety of a target molecule or other biomarker located, for example, in an organism, tissue, cell or extracellular fluid, or any combination thereof. Biomarkers include, but are not limited to, peptide targeting agents such as, for example, integrin targeting agents, proteins, antibodies, drugs, peptidomimetics, glycoproteins, glycolipids, glycans, lipids, nucleic acids, carbohydrates, phospholipids and the like. Biomarkers include, but are not limited to, organic molecules comprised of a mass of 5,000 daltons or less. [0072] In a third aspect, the invention resides in a method of preparing a compound of formula (I) comprising the steps of: a. providing a compound of formula (II):

Formula (II) wherein,

Ri and R ₂ are independently selected from the group consisting of hydrogen, hydroxyl, amine, amide, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C12 alkoxy, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl,

R ₃ , R ₄ , R ₅ , R ₆ are independently selected from the group consisting of hydrogen, hydroxyl, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C8 acryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;

Ei and E ₂ are independently selected from S, 0, or Se;

M is a transition metal ion, or a radioisotope thereof;

X is a leaving group; and b. substituting X with ¹⁸ F or ¹⁹ F. [0073] As previously mentioned, one advantage of the present invention lies in the ease of preparation of the compound of formula (I). The compound of formula (I) is attractive since the radioactive isotope ¹⁸ F can be introduced at a late stage of the synthesis. The simple preparation of the compound of formula (I) also alleviates the problem associated with using radionuclides with shorter half-lives, and the problem associated with the loss of efficacy due to a delay in administration. The reduced time between production and administration opens the possibility of using other radionuclides in imaging agents.

[0074] It will be appreciated that the formation of a compound of formula (II) is, generally, known in the art and the following merely describes one possible method for the preparation thereof. It will also be appreciated by the person skilled in the art that R-i, R ₂ , R3, R ₄ , R5 and R ₆ are selected based on the starting material and the desired lipophilic profile. For example, if Ri and R ₂ are phenyl moieties; R ₃ , R ₄ , R ₅ and R ₆ are hydrogens; Ei and E ₂ are sulfur; and M is gallium, then the starting material is diphenylglyoxal. Alternatively, if Ri and R ₂ are ethyl moieties; R ₃ , R ₄ , R ₅ and R ₆ are hydrogens, Ei and E ₂ are sulfur, and M is gallium, then the starting material is diethylglyoxal.

[0075] A solution of a glyoxal in methanol and hydrochloric acid was treated with thiosemicarbazide to give a thiosemicarbazone. In one example, a suspension of the thiosemicarbazone in methanol was then treated with sodium methoxide, and metal chloride to give a thiosemicarbazone-metal chloride complex. It will be appreciated that other alkoxides and alkanols can be used to form the thiosemicarbazone metal complex. The thiosemicarbazone-metal chloride complex was treated with silver nitrate, followed by treatment with potassium fluoride to give the thiosemicarbazone-metal fluoride complex. It is submitted that the methoxide and ethoxide substituted metal complex are stable. This is advantageous as the methoxide and ethoxide precursor metal complex can be easily converted to the leaving group substituted metal complex. As such, these compounds can be stored prior to radiolabeling. [0076] The leaving group will be understood by a person skilled in the art as a molecular fragment that can be substituted in a substitution reaction. A person skilled in the art will also understand that good leaving groups are generally weak bases and have a low or negative pKa value. Suitable leaving groups include chloride, bromide, iodide, nitrate, acetate, citrate, sulfonate, and triflate. It will be appreciated by a person skilled in the art that this list merely exemplifies the types of leaving groups that can be utilized and is not an exhaustive list.

[0077] A thiosemicarbazone-metal halogen complex can be converted to a thiosemicarbazone-metal nitrate complex by treating the halogen complex with silver nitrate. In one embodiment, the compound of formula (II) is treated with AgN0 ₃ .

[0078] The nitrate group in the thiosemicarbazone-metal nitrate complex can then be substituted with a radionuclide to give a compound of formula (I) by treating the nitrate complex with the potassium or sodium salt of ¹⁸ F or ¹⁹ F. These crude mixtures are then purified to give the compound of formula (I) that is ready for administration. In certain embodiments, the halogen is ¹⁸ F. Suitable salts of the halogen are selected from the group consisting of K ¹⁸ F, Na ¹⁸ F, R ₄ N ¹⁸ F, [K(kryptofix)] ¹⁸ F, Na(18-6-crown ether)] ¹⁸ F.

[0079] In a sample procedure of converting the thiosemicarbazone-metal halogen complex to a thiosemicarbazone-metal fluoride complex, the thiosemicarbazone-metal halogen complex was dissolved in methanol. Silver nitrate was then added to this mixture and stirred. The resultant solution was allowed to settle (silver halide settled out) and the liquid was transferred to another vial. The methanol was then evaporated or removed and the resultant residue was dissolved in dimethyl sulfoxide (DMSO). Another vessel was charged with potassium carbonate, Kryptofix 222, acetonitrile and ¹⁸ F aqueous solution. This vessel was sealed and heated under inert atmosphere, and allowed to dry. To this dry mixture was added the thiosemicarbazone-metal nitrate complex pre-dissolved in dimethylsulfoxide, and stirred and heated to form the thiosemicarbazone-metal fluoride complex.

[0080] In order to determine the lipophilicity of the compound, a fresh batch of fluoride gallium complex was made using the exchange method described above. The gallium fluoride complex was dissolved in an octanol/water mixture and stirred vigorously for 20 minutes. The resulting layers were separated and analyzed using a UV spectrometer. The ratio of the UV absorbance at 475 nm for each of the layers was used to determine the partition coefficient value. The aqueous solution, after storing for 48 hours, showed no significant decomposition, as determined by its UV spectral characteristics.

[0081 ] Additionally, to test the stability of these compounds, the compounds (10 mg) were added to water (10 ml_, pH = 6.4), and the resulting mixture was stirred for 30 minutes. The compounds did not dissolve into solution. Furthermore, the compounds were dissolved in dimethyl sulfoxide and left to stand undisturbed for three weeks. The ¹ H NMR analysis showed no decomposition, and indicated that these compounds are stable.

[0082] In an embodiment, the compound of formula (II) is treated with a fluoride salt and a base.

[0083] In one embodiment, the compound of formula (II) is treated with K ₂ C0 ₃ /Kryptofix 222/ ¹⁸ F.

[0084] In a fourth aspect, the invention resides in a method of medical imaging of a patient comprising the steps of: a. administering a compound of formula (I) to the patient

Formula (I) wherein,

Ri and R ₂ are independently selected from the group consisting of hydrogen, hydroxyl, amine, amide, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C12 alkoxy, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;

R ₃ , R ₄ , R ₅ , R ₆ are independently selected from the group consisting of hydrogen, hydroxyl, halogen, PEG, N-PEG, substituted or unsubstituted C1 -C12 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1 -C8 acyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, and substituted or unsubstituted C1 -C12 haloalkyl;

Ei and E ₂ are independently selected from S, 0, or Se; F is ¹⁸ F or ¹⁹ F;

M is a transition metal ion, or a radioisotope thereof; and b. detecting the radioactive decay from the ¹⁸ F or the transition metal radioisotope.

[0085] The compound of formula (I) may be substantially as described in any one or more embodiments of the first aspect.

[0086] Once the compound of formula (I) has been administered to the patient, the decay of the radionuclide allows the body to be imaged. The compound should be administered quickly after production to ensure that any loss of efficacy is minimized. [0087] It will be appreciated that the compound of formula (I) can also be linked to a biomarker so that a particular pathological or physiological process, or disease can be identified. The inclusion of a biomarker allows the imaging technique to probe a particular diseased state or another physiological state of the subject. The biomarker linked compound can then bind or adhere to a target area to improve the imaging ability of the compound. EXAMPLES

Sample preparation of Ri,R _∑ thiosemicarbazone

^R l ^R :

\ / N N

0 0 I IN Ni l

^■ Nil,

S S

[0088] Concentrated hydrochloric acid (2ml) was added to a flask containing the appropriate amount of Ri, R2-glyoxal and methanol (50 ml). This was stirred at room temperature to form a homogenous solution. A solution of thiosemicarbazide (dissolved in methanol containing 2N hydrochloric acid) was added, and the mixture stirred at room temperature for 3 days, which resulting in the formation of a white precipitate. The precipitated thiosemicarbazone was filtered, washed with methanol and dried under vacuum.

Ri, R ₂ = hydrogen: 2.15g, ¹ H NMR (d ₆ -DMSO) δ ppm: 1 1 .67 (bs, 2H), 8.30 (bs, 2H), 7.87 (bs, 2H), 7.71 (s, 2H); ¹³ C NMR (d ₆ -DMSO):5 ppm: 178.1 , 140.6; ¹⁵ N NMR (de-DMSO) δ ppm: 1 10.3 (NH ₂ ), 175.5(NH).

Ri, R ₂ = methyl: 2.4g; ¹ H NMR (d ₆ -DMSO) 5ppm: 10.20 (bs, 2H), 8.39 (bs, 2H), 7.84 (bs, 2H), 2.13 (s, 6H); ¹³ C NMR (d ₆ -DMSO) δ ppm: 178.9, 148.3, 1 1 .6; ¹⁵ N NMR (de-DMSO) δ ppm: 1 10.8 (NH ₂ ), 168.3(NH), 317.6(C=N);

Ri, R ₂ = ethyl : 4.98g , ¹ H NMR (d ₆ -DMSO):6 ppm: 10.32 (bs, 2H), 8.36 (bs, 2H), 7.73 (bs, 2H), 2.79 (q, 4H, J=7.4Hz); 0.87 (t, 6H, J=7.4Hz); ¹³ C NMR (d ₆ -DMSO) δ ppm 1 1 1 .0 (NH ₂ ), 166.0 (NH), 313.5 (C=N) ¹⁵ N NMR (d ₆ -DMSO) δ ppm: 1 1 1 .0 (NH ₂ ), 166.0 (NH), 313.5 (C=N);

Ri = methyl, R ₂ = ethyl:.4.5g, IR: 3417, 3203, 3149, 2984, 1598, 1506, 1446, 1365, 1289, 1243, 1 154, 1085, 1057, 987, 865, 841 , 792 cm ^"1 ; ¹ H NMR (de- DMSO): δ ppm: 10.33 (s, 1 H), 10.20 (s, 1 H), 8.40 (s, 1 H), 8.39 (s, 1 H), 7.82(s, 1 H), 7.74 (s, 1 H), 2.84 (q, 2H), 2.14 (s, 3H), 0.89 (t, 3H); ¹³ C NMR (d ₆ -DMSO) δ ppm: 178.9, 178.8, 152.2, 147.3, 16.9, 1 1 .7, 1 1 .0; ¹⁵ N NMR (d ₆ -DMSO):5 ppm: 317.2, 315.7, 167.8, 165.9, 1 10.8, 1 10.2.

Ri, R ₂ = phenyl. 6.8g, IR: 3415, 3226, 3136, 2950, 1584, 1474, 1442, 1240, 1 133, 1069, 1005, 922, 906, 865, 828, 763 cm- ¹ ; ¹ H NMR (d ₆ -DMSO) δ ppm: 9.84 (bs, 2H), 8.67 (bs, 2H), 8.38 (bs, 2H), 7.72 (m, 4H), 7.43-7.38 (m,6H); ¹³ C NMR (de-DMSO) δ ppm: 179.1 , 140.5, 133.1 , 130.2, 128.4, 126.7; ¹⁵ NNMR (d ₆ - DMSO):5 ppm 167.8,1 13.8.

Sample preparation of diphenyl thiosemicarbazone chloride complex

[0089] A suspension of a diphenyl thiosemicarbazone (5 mmol) in methanol (40 ml) was added to a round bottomed flask and the contents were stirred. Sodium methoxide solid (10 mmol) was introduced resulting in a yellow solution. After 10 minutes of stirring, gallium chloride (5 mmol) was added which resulted in an exothermic reaction and a deep orange solution. The contents were refluxed for 8 hours and the mixture was cooled to room temperature. The product which precipitated out as an orange solid during the reaction was filtered, and washed with methanol.

Yield: 1 .98g (86%); IR: 3447, 3326, 3273, 3067, 1627, 1582, 1521 , 1493, 1462, 1428, 1335, 1315, 1288, 1273, 1210, 1 166, 1 105, 1069, 1051 , 1025, 1001 , 981 , 887, 783 cm ^"1 ; ¹ H NMR (d ₆ -DMSO) δ ppm: 8.14 (bs, 4H), 7.26 (m,6H), 7.18 (m, 4H); ¹³ C NMR (d ₆ -DMSO) δ ppm: 174.8, 142.7, 131 .8, 129.5, 129.1 , 127.7; ¹⁵ NNMR(d ₆ -DMSO) δ ppm: 304.5, 253.7, 107.9. Mass spectrum: El/ms: 461 (M ⁺ ),

Sample preparation of diphenyl thiosemicarbazone gallium methoxide complex [0090] A suspension of diphenyl thiosemicarbazone (0.445g, 1 .25 mmol) in methanol (40 ml) was added to a round bottomed flask and stirred. Sodium methoxide (s, 0.270 g, 5 mmol) was introduced and resulted in a deep yellow solution. After stirring (10 minutes), gallium nitrate (0.32 g, 1 .25 mmol) was added resulting in an exothermic reaction and a deep orange solution. The mixture was refluxed for 8 hours and the mixture was cooled to room temperature. The product precipitated out as an orange/red solid which was filtered, washed with methanol. (Note: the methoxide complex in d6-DMSO showed multiple peaks for the elimination of MeOH from the coordinating complex) : ¹ HNMR(d6-DMSO) δ ppm: 8.0-7.18 (m, 10H), 4.10-4.07 (q, MeOH, hydrogen bonded), 3.36-3.31 (d, MeO hydrogen bonded to MeOH), 3.17-3.16 (d, 3H, hydrogen bonded MeOH); ¹³ C NMR (de-DMSO) δ ppm: 175.9, 143.2, 132.0, 129.5, 128.7127.6, 127.5, 127.2, 51 .6, 48.6.

Sample preparation of diphenyl thiosemicarbazone gallium nitrate complex and ¹⁸ F radiolabelling

[0091 ] Pure water (-0.7 ml_) enriched to >98% H ₂ ¹⁸ O was irradiated with 18 MeV protons at a beam current of 14 μΑ for 8 min to produce 4.5 GBq of fluorine-18. The aqueous [ ¹⁸ F] fluoride was transferred from the cyclotron target to a 10-mL glass-receiving vial located in a hot-cell via a 1 /16"diameter ETFE tubing with a length of ~20m under helium pressure. The receiving vial was measured for radioactive content in a dose calibrator housed within the hot-cell before delivery into a lead pot. The lead pot was then manually transferred to a fume cabinet where aliquots of the aqueous [ ¹⁸ F] fluoride were taken for radiolabeling.

[0092] Diphenyl thiosemicarbazone gallium chloride was treated with silver nitrate in methanol for 30 minutes to generate the diphenyl thiosemicarbazone gallium nitrate complex. An aliquot of this reaction was transferred to another reaction vial. The methanol was removed via evaporation by heating the solution with a steady flow of nitrogen. The residue was redissolved in dimethyl sulphoxide and added to a vial containing [ ¹⁸ F]fluoride (10 μΙ_, 88 MBq), kryptofix 222 (1 .2mg) and potassium carbonate (0.7mg). The vial was heated at 40-50°C for 3 minutes. Radio-HPLC of the crude reaction mixture confirmed formation of [ ¹⁸ F]diphenylthiosemicarbazone gallium fluoride which co-eluted at the same retention time as [ ¹⁹ F]diphenylthiosemicarbazone gallium fluoride (retention time of 15.6 minutes).

HPLC: Zorbax Eclipse Plus 150 4.6mm (5μιη) (Mobile phase A = 0.1 %TFA in water; Mobile phase B = 100% MeCN). Flow rate 1 mL/min. 0 min (10%B), 30 min (90%B), 40 min (90%B), 43 min (10%B), 45 min (10%B). NMR data for diphenyl thiosemicarbazone gallium ethoxide complex

¹ H NMR (aVDMSO) δ ppm: (note: the ethoxide complex in d6-DMSO showed multiple peaks for the elimination of EtOH from the coordinating complex: ¹ H NMR (de-DMSO) δ ppm:7.6-7.0 (m,10H), 4.32(EtOH,OH), 3.55(q, EtOH), 3.44(q, EtO), 1 .24(t,CH ₃ CH ₂ OH), 1 .04(t,3H,EtO); ¹³ C NMR (d ₆ -DMSO) δ ppm: 181 .2, 142.8, 141 .8, 137.7, 133-126.0(multiple peaks), 58.7(EtO), 56.02 (EtOH),18.6(EtO), 14.9(EtOH).

Sample preparation of halogen exchange reactions

Diphenylthiosemicarbazone gallium fluoride complex [0093] Diphenylthiosemicarbazone gallium chloride (0. 0459g, 0.1 mmol) was suspended in methanol (15 ml) in a 20 ml vial. The blood red suspension was stirred (10 minutes) followed by the addition of silver nitrate (0.017g, 0.1 mmol), and shaken (2 minutes). The solution was then vigorously stirred (30 minutes), resulting in the formation of an orange solution and silver chloride precipitate. The contents were allowed to settle and the orange supernatant was transferred into another vial. Potassium fluoride (0.0058g, 0.1 mmol) was added to the supernatant and yielded a deep red solution. The mixture was stirred (10 minutes) at room temperature, and the solvent was evaporated to obtain an orange-red residue. An NMR spectrum of the product revealed the formation of fluoride complex: ¹ H NMR (d ₆ -DMSO) δ ppm:8.07-7.15 (m,10H), 4.10-4.09 (t, MeOH, hydrogen bonded with F), 3.17-3.16 (d, MeO hydrogen bonded); ¹³ C NMR (de-DMSO) δ ppm: 175.6, 141 .0, 132.2, 131 .9,129.1 ,127.8, 48.7; ¹⁹ F NMR (d6-DMSO) δ ppm: -93.7 ( relative to TFA 1 % standard capillary insert standard at 0 ppm), 0.021 g (yield 47.7%) Diphenyl thiosemicarbazone gallium iodide complex

[0094] The method was completed as above, with the exception of potassium iodide being used.

¹ H NMR (de-DMSO) δ ppm: 8.07(bs), 7.15-7.28 (m, Ar); 4.10 (bs,MeO hydrogen bond), 3.16 (s, MeO); ¹³ C NMR (d ₆ -DMSO) δ ppm: 175.8, 141 .2, 131.9, 129.5, 127.8, 48.6; 0.033g, (yield 61 .0%)

Cold Thin Layer Chromatography Determination [0095] After preparation of the complex using the exchange discussed hereinabove, the gallium fluoride complex was spotted on a thin layer chromatography silica gel plate and eluted with 10% ammonium acetate/methanol (1 :1 ) solution. The observed R _f value of the product was 0.86. The chloro compound and the iodo compound of the gallium complex showed a similar R _f value to the gallium fluoride complex. The NMR spectroscopy showed the ¹⁹ F NMR signal for the fluoro compound and did not show the other two compounds, and confirmed that the fluoride complex had been formed. X-Ray characterization data for diphenyl thiosemicarbazone gallium methoxide complex and diphenyl thiosemicarbazone gallium chloride complex

13<=1<=13 19<=1<=19

Reflections collected 6311 9215

Independent reflections 2920 [R(int) = 0.0758] 3348 [R(int) = 0.0553]

Completeness to theta = 98.2 % 98.4 %

62.45°

Absorption correction Semi-empirical from Semi-empirical from

equivalents equivalents

Max. and min. 1 and 0.80489 1 and 0.47098

transmission

2

Refinement method Full-matrix least-squares on F Full-matrix least-squares on

2

F

Data / restraints / 2920 / 0 / 235 3348 / 0 / 265

parameters

Goodness-of-fit on F^ 1.092 1.055

Final R indices Rl = 0.0448, wR2 = 0.1092 Rl = 0.0371, wR2 = 0.0931 [I>2sigma(I)]

R indices (all data) Rl = 0.0675, wR2 = 0.1482 Rl = 0.0446, wR2 = 0.0988

Largest diff. peak and 0.622 and -0.874 e.A ^"3 0.619 and -0.411 e.A ^"3 hole

[0096] The single crystal X-ray structure of the diphenyl thiosemicarbazone gallium chloride complex is shown in FIG 3, and the single crystal X-ray structure of the diphenyl thiosemicarbazone gallium methoxide complex is shown in FIG 4. Please note that a single methanol molecule co-crystallized in the diphenyl thiosemicarbazone gallium methoxide complex crystal.

[0097] Experimental measurement of lipophilicity of diphenyl thiosemicarbazone gallium fluoride complex

[0098] The log P value was determined using standard literature procedures (Sangster J. Octanol-water Partition Coefficients: Fundamentals and Physical Chemistry. Wiley; New York: 1997; Hansch C, Fujita T. J Am Chem Soc. 1964(86) pp. 1616-1626; Leo A, Hansch C, Elkins D. Chemical Reviews. 1971 (71 ) pp. 525-616). [0099] Using the above methodology, the partition coefficient measurement of diphenyl thiosemicarbazone gallium fluoride complex using the absorbance at 475nm in octanol/water mixture was 1 1 , providing a logP value of +1 .05.

[00100] The compound of formula (I) allows for different radionuclides to be utilized and it should be clear that the present invention alleviates the problems associated with the prior art imaging agents by lessening our dependency on ^99m Tc. This is made possible by the simple synthetic route of the compounds of formula (I). The synthetic route does not require lengthy purification steps and can be prepared in a standard laboratory to reduce the time between synthesis and administration.

Imaging Studies

[00101 ] Dynamic PET imaging studies was completed with [ ¹⁸ F]diphenylthiosemicarbazonegallium fluoride on two mice. The results indicate that there was uptake of the tracer in the brain as anticipated. [00102] The dynamic PET imaging studies of [ ¹⁸ F]diphenylthiosemicarbazonegallium fluoride in the two mice showed rapid uptake, where peak uptake was observed at approximately 2 minutes. This test was completed with an injected dose/gram of 2% to 3%, and is a good result for a brain imaging agent. In this regard, the profile of the uptake is summarized in the time activity curves shown in FIGs 1 and 2.

[00103] Additionally, a snapshot of the uptake in the mice at 30 minutes, from the imaging studies, is presented in Tables 1 and 2 below:

ID: 130000

Ml (5634)

weight:30g

30 min

Mean (nCi/cc) nCi/organ

Mean decay Volume (decay

Ml (nCi/cc) corrected %ID/g (mm ³ ) corrected) % ID/organ

Whole body 1804.8 2180 1.677 63219.8 137836 106.03

Heart 16237.2 19615 15.089 213.2 4182 3.22

Kidney Right 8102.4 9788 7.529 124.4 1218 0.94

Kidney Left 11106.5 13417 10.321 90.8 1218 0.94 Bladder 6135.3 7412 5.701 100.6 746 0.57

Liver 15919.7 19232 14.794 1739.4 33452 25.73

Brain 1333.5 1611 1.239 59.5 96 0.07

* nCi/cm ³ of tissue can be approximate to

nCi/g

Table 1 : Snapshot of the uptake of [ ¹⁸ F]diphenylthiosemicarbazonegallium in a first mouse at 30 minutes

ID: 87000

M3 (5635)

weight:28g

* nCi/cm ³ of tissue can be approximate to

nCi/g

Table 2 : Snapshot of the uptake of [ ¹⁸ F]diphenylthiosemicarbazonegalli

second mouse at 30 minutes

[00104] The data for the two mice show injected dose/gram greater than 1 % at 30 minutes. This biodistribution data is consistent with the dynamic imaging data.

[00105] The above description of various embodiments of the present invention is provided for purposes of description to one of ordinary skill in the related art. It is not intended to be exhaustive or to limit the invention to a single disclosed embodiment. As mentioned above, numerous alternatives and variations to the present invention will be apparent to those skilled in the art of the above teaching. Accordingly, while some alternative embodiments have been discussed specifically, other embodiments will be apparent or relatively easily developed by those of ordinary skill in the art. Accordingly, this invention is intended to embrace all alternatives, modifications and variations of the present invention that have been discussed herein, and other embodiments that fall within the spirit and scope of the above described invention.