¹⁸ F COMPOUNDS FOR CANCER IMAGING AND

METHODS FOR THEIR USE

CROSS REFERENCE TO RELATED APPLICATIONS

This Application claims the benefit of U.S. Provisional Application No. 62/063,650, filed October 14, 2014, which is hereby incorporated by reference in its entirety for all purposes.

STATEMENT OF GOVERNMENT INTEREST

This invention was made in part with government support under Grant No. 2R01

CA105304 awarded by the National Cancer Institute. The United States Government has certain rights in this invention.

BACKGROUND

This invention relates to radiolabeled compounds, their uses and methods for imaging tumors, including prostate cancer tumors. In particular the invention relates to radioactive ^I8 F compounds and their use as an imaging tool in prostate cancer. The disclosed compounds find utility in any number of imaging applications, including imaging of splice variants in prostate cancers, including all stages and androgen dependent, androgen-sensitive and castration-resistant prostate cancers (also referred to as hormone refractory, androgen- independent, androgen deprivation resistant, androgen ablation resistant, androgen depletion-independent, castration-recurrent, and anti-androgen-recurrent). Androgens mediate their effects through the androgen receptor (AR). Androgens play a role in a wide range of developmental and physiological responses and are involved in male sexual differentiation, maintenance of spermatogenesis, and male gonadotropin regulation (R. K. Ross, G. A. Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E. Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355-361 (1999); A. A. Thomson, Reproduction 121, 187-195 (2001); N. Tanji, K. Aoki & M. Yokoyama, Arch Androl 47, 1-7 (2001)). Several lines of evidence show that androgens are associated with the development of prostate carcinogenesis. Firstly, androgens induce prostatic carcinogenesis in rodent models (R. L. Noble, Cancer Res 37, 1929-1933 (1977); R. L. Noble, Oncology 34, 138-141 (1977)) and men receiving androgens in the form of anabolic steroids have a higher incidence of prostate cancer (J. T. Roberts & D. M. Essenhigh, Lancet 2, 742 (1986); J. A. Jackson, J. Waxman & A. M. Spiekerman, Arch Intern Med 149, 2365-2366 (1989); P. D. Guinan, W. Sadoughi, H. Alsheik, R. J. Ablin, D. Alrenga & I. M. Bush, Am J Surg 131, 599-600 (1976)). Secondly, prostate cancer does not develop if humans or dogs are castrated before puberty (J. D. Wilson & C. Roehrborn, J Clin Endocrinol Metab 84, 4324-4331 (1999); G. Wilding, Cancer Surv 14, 113-130 (1992)). Castration of adult males causes involution of the prostate and apoptosis of prostatic epithelium while eliciting no effect on other male external genitalia (E. M. Bruckheimer & N. Kyprianou, Cell Tissue Res 301, 153-162 (2000); J. T. Isaacs, Prostate 5, 545-557 (1984)). This dependency on androgens provides the underlying rationale for treating prostate cancer with chemical or surgical castration (androgen ablation).

Androgens also play a role in female cancers. One example is ovarian cancer where elevated levels of androgens are associated with an increased risk of developing ovarian cancer (K. J. Helzlsouer, A. J. Alberg, G. B. Gordon, C. Longcope, T. L. Bush, S. C. Hoffman & G. W. Comstock, JAMA 274, 1926-1930 (1995); R. J. Edmondson, J. M. Monaghan & B. R. Davies, Br J Cancer 86, 879-885 (2002)). The AR has been detected in a majority of ovarian cancers (H. A. Risch, J Natl Cancer Inst 90, 1774-1786 (1998); B. R. Rao & B. J. Slotman, Endocr Rev 12, 14-26 (1991); G. M. Clinton & W. Hua, Crit Rev Oncol Hematol 25, 1-9 (1997)), whereas estrogen receptor-alpha (ERa) and the progesterone receptor are detected in less than 50% of ovarian tumors.

The only effective treatment available for advanced prostate cancer is the withdrawal of androgens which are essential for the survival of prostate epithelial cells. Androgen ablation therapy causes a temporary reduction in tumor burden concomitant with a decrease in serum prostate-specific antigen (PSA). Unfortunately prostate cancer can eventually grow again in the absence of testicular androgens (castration-resistant disease) (Huber et al 1987 Scand J. Oral Nephrol. 104, 33-39). Castration-resistant prostate cancer is biochemically characterized before the onset of symptoms by a rising titre of serum PSA (Miller et al 1992 J. Urol. 147, 956-961). Once the disease becomes castration-resistant most patients succumb to their disease within two years.

The AR has distinct functional domains that include the carboxy-terminal ligand-binding domain (LBD), a DNA-binding domain (DBD) comprising two zinc finger motifs, and an N-terminus domain (NTD) that contains one or more transcriptional activation domains. Binding of androgen (ligand) to the LBD of the AR results in its activation such that the receptor can effectively bind to its specific DNA consensus site, termed the androgen response element (ARE), on the promoter and enhancer regions of "normally" androgen regulated genes, such as PSA, to initiate transcription. The AR can be activated in the absence of androgen by stimulation of the cAMP-dependent protein kinase (PKA) pathway, with interleukin-6 (IL-6) and by various growth factors (Culig et al 1994 Cancer Res. 54, 5474-5478; Nazareth et al 1996 J. Biol. Chem. 271, 19900-19907; Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 38087-38094). The mechanism of ligand-independent transformation of the AR has been shown to involve: 1) increased nuclear AR protein suggesting nuclear translocation; 2) increased AR/ARE complex formation; and 3) the AR-NTD (Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 38087-38094). The AR may be activated in the absence of testicular androgens by alternative signal transduction pathways in castration-resistant disease, which is consistent with the finding that nuclear AR protein is present in secondary prostate cancer tumors (Kim et al 2002 Am. J. Pathol. 160, 219-226; and van der Kwast et al 1991 Inter. J. Cancer 48, 189-193).

Available inhibitors of the AR include nonsteroidal antiandrogens such as bicalutamide (Casodex™), nilutamide, flutamide, investigational drugs MDV3100 and ARN- 509, and the steroidal antiandrogen, cyproterone acetate. These antiandrogens target the LBD of the AR and predominantly fail presumably due to poor affinity and mutations that lead to activation of the AR by these same antiandrogens (Taplin, M.E., Bubley, G.J., Kom Y.J., Small E.J., Uptonm M., Rajeshkumarm B., Balkm S.P., Cancer Res., 59, 2511-2515 (1999)). These antiandrogens would also have no effect on the recently discovered AR splice variants that lack the ligand-binding domain (LBD) to result in a constitutively active receptor which promotes progression of androgen-independent prostate cancer (Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ., Cancer Res 68, 5469-77, 2008; Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung HJ, Brodie AM, Edwards J, Qiu Y., Cancer Res. 69, 2305-13, 2009; Hu et al 2009 Cancer Res. 69, 16- 22; Sun et al 2010 J Clin Invest. 2010 120, 2715-30).

Conventional therapy has concentrated on androgen-dependent activation of the AR through its C-terminal domain. Recent studies developing antagonists to the AR have concentrated on the C-terminus and specifically: 1) the allosteric pocket and AF-2 activity (Estebanez-Perpina et al 2007, PNAS 104, 16074-16079); 2) in silico "drug repurposing" procedure for identification of nonsteroidal antagonists (Bisson et al 2007, PNAS 104, 11927 - 11932); and coactivator or corepressor interactions (Chang et al 2005, Mol Endocrinology 19, 2478-2490; Hur et al 2004, PLoS Biol 2, E274; Estdbanez-Perpifia et al 2005, JBC 280,

8060-8068; He et al 2004, Mol Cell 16, 425-438).

The AR-NTD is also a target for drug development (e.g. WO 2000/001813), since the

NTD contains Activation-Function-l (AF_1) which is the essential region required for AR transcriptional activity (Jenster et al 1991. Mol Endocrinol. 5, 1396-404). The AR-NTD importantly plays a role in activation of the AR in the absence of androgens (Sadar, M.D.

1999 J. Biol. Chem. 274, 7777-7783; Sadar MD et al 1999 Endocr Relat Cancer. 6, 487-502;

Ueda et al 2002 J. Biol. Chem. 277, 7076-7085; Ueda 2002 J. Biol. Chem. 277, 38087-38094;

Blaszczyk et al 2004 Clin Cancer Res. 10, 1860-9; Dehm et al 2006 J Biol Chem. 28, 27882-93; Gregory et al 2004 J Biol Chem. 279, 7119-30). The AR-NTD is important in hormonal progression of prostate cancer as shown by application of decoy molecules (Quayle et al 2007, Proc Natl Acad Sci USA. 104, 1331-1336).

While the crystal structure has been resolved for the AR C-termimus LBD, this has not been the case for the NTD due to its high flexibility and intrinisic disorder in solution (Reid et al 2002 J. Biol. Chem. 277, 20079-20086) thereby hampering virtual docking drug discovery approaches. Compounds that modulate AR include the bis-phenol compounds disclosed in published PCT WO 2010/000066, which is hereby incorporated by reference in its entirety, to the British Columbia Cancer Agency Branch and The University of British

Columbia.

In addition to compounds which modulate AR, compounds and methods for imaging prostate cancers are useful research and treatment tools. In this regard, positron emission tomography (PET) is an often used imaging technique for non-invasive identification of tumors. In PET imaging, the distribution of a radioisotope (e.g., ¹⁸ F) in the body can be determined. Thus incorporating ¹⁸ F into compounds which concentrate in tumor sites offers potential for diagnosis, staging, and monitoring treatment of cancers. However, no effective method for imaging of prostate cancers, in particular imaging of splice variants in castrate recurrent prostate cancers is available.

While significant advances have been made in this field, there remains a need for improved imaging agents In particular, methods and compounds suitable for imaging certain prostate cancers are needed. The present invention fulfills these needs, and provides other related advantages. BRIEF SUMMARY

Some embodiments of the compounds described herein may be used for diagnostic purposes to investigate cancer. In particular, the compounds are useful for imaging diagnostics in cancer. In some embodiments, such imaging allows for the detection and/or location of cancer sites (e.g., tumor sites). Furthermore, these compounds may be used individually or as part of a kit for such purposes.

The present disclosure is based in part on the surprising discovery that the compounds described herein, may be used to modulate AR activity either in vivo or in vitro for both research and therapeutic uses. Accordingly, the compounds are useful for imaging certain cancers, including prostate cancer since certain embodiments of the compounds localize in prostate tumor sites. Other imaging agents are androgen mimics; however, in one embodiment, the compounds are useful for imaging splice site variants. The AR may be mammalian. Alternatively, the androgen receptor may be human. The prostate cancer may be castration-resistant prostate cancer. The prostate cancer may be androgen-dependent prostate cancer.

In accordance with one embodiment, there is provided a compound having a structure of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ , R ² , R ³ , R ⁴ , Z, X and n are as defined herein, and wherein the compound comprises at least one ^I8 F moiety.

In other embodiments pharmaceutical compositions comprising a compound of structure (I) are provided. Methods employing such pharmaceutical compositions for imaging cancer are also provided.

In another embodiment, the present disclosure provides compounds useful in the preparation of compounds of structure (I), such compounds have the following structure (II):

or a salt or stereoisomer thereof, wherein R ⁵ , R ⁶ , R ⁷ , R ⁸ , Z ² , X ² and n are as defined herein. Methods employing compounds of structure (II) for preparation of compounds of structure (I) are also provided.

These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

I. Definitions

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well- known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is, as "including, but not limited to." Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment ¹ ' in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.

The terms below, as used herein, have the following meanings, unless indicated otherwise:

"Alkyl" refers to a straight or branched hydrocarbon chain radical which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 6 carbon atoms is a C ₁ -C ₆ alkyl and an alkyl comprising up to 5 carbon atoms is a C ₁ -C ₅ alkyl. A C ₁ -C ₅ alkyl includes C ₅ alkyls, C ₄ alkyls, C ₃ alkyls, C ₂ alkyls and C ₁ alkyl (i.e., methyl) and includes, for example, and without limitation, saturated C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl and C ₂ -C ₅ alkynyl. Non-limiting examples of saturated C ₁ -C ₅ alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl and n- pentyl. Non-limiting examples of C ₂ -C ₅ alkenyl include vinyl, allyl, isopropenyl, 1-propene- 2-yl, 1-butene-l-yl, l-butene-2-yl, l-butene-3-yl, 2-butene-l-yl, 2-butene-2-yl, penteneyl and the like. Non-limiting examples of C ₂ -C ₅ alkynyl include ethynyl, propynyl, butynyl, pentynyland the like. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted with one or more fluorine atoms (i.e., a hydrogen atom in the alkyl group may be replaced with fluorine). A C ₁ -C ₆ alkyl includes all moieties described above for C ₁ -C ₅ alkyls but also includes C ₆ alkyls.

"Aryl" means an aromatic carbocyclic moiety such as phenyl, naphthyl and the like. An aryl moiety may be optionally substituted, for example with C ₁ -C ₆ alkyl,

"Hydroxy" or "hydroxyl" refers to the -OH radical.

"Fluoro" and "chloro" refer to fluorine (F) and chlorine (CI) substituents, respectively, and also include radioisotopes of the same. " ^,8 F" refers to the radioactive isotope of fluorine having atomic mass 18. "F" or " ¹⁹ F" refers to the abundant, nonradioactive fluorine isotope having atomic mass 19. The compounds of structure (I) comprise at least one ^{l 8} F moiety. Throughout the present application, where structures depict a ¹⁸ F moiety at a certain position it is meant that the F moiety at this position is enriched for ¹⁸ F. In other words, the compounds contain more than the natural abundance of ^l8 F at the indicated position(s). It is not required that the compounds comprise 100% ¹⁸ F at the indicated positions, provided ¹⁸ F is present in more than the natural abundance. Typically the ¹⁸ F isotope is enriched to greater than 50%, greater than 60%, greater than 70%, greater than, 80% or greater than 90%, relative to ¹⁹ F. As used herein, the symbol (hereinafter may be referred to as "a point of attachment bond") denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example. indicates that the chemical entity "XY" is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entit may be specified by inference. For example, the compound CH ₃ -R ³ , wherein R ³ is H or infers that when R ³ is "XY", the point of attachment bond is the same bond as the bond by which R ³ is depicted as being bonded to C¾.

II. Compounds and Methods

Androgen ablation therapy causes a temporary reduction in prostate cancer tumor burden, but the malignancy will begin to grow again in the absence of testicular androgens to form castrate resistant prostate cancer (CRPC). A rising titer of serum prostate-specific antigen (PSA) after androgen ablation therapy indicates biochemical failure, the emergence of CRPC, and re-initiation of an androgen receptor (AR) transcription program. Most patients succumb to CRPC within two years of biochemical failure.

AR is a transcription factor and a validated target for prostate cancer therapy. Current therapies include androgen ablation and administration of antiandrogens. Most CRPC is suspected to be AR-dependent. AR has distinct functional domains that include the C- terminus ligand-binding domain (LBD), a DNA-binding domain (DBD), and an amino- terminal domain (NTD). AR NTD contains the activation function- 1 (AF-1) that contributes most of the activity to the AR. Recently, splice variants of the AR that lack the LBD have been reported in prostate cancer cell lines (VCaP and 22Rvl), and in CRPC tissues. To date more than 20 splice variants of AR have been detected. Splice variants V7 and V567es are clinically relevant with levels of expression correlated to poor survival and CRPC. AR V567es is solely expressed in 20% of metastases. Abiraterone resistance is associated with expression of AR splice variants. MDV3100 also increases levels of expression of these constitutively active AR splice variants. These splice variants lack LBD and thereby would not be inhibited by current therapies that target the AR LBD such as antiandrogens or androgen ablation therapy. A single patient with advanced prostate cancer can have many lesions throughout the body and skeleton and each tumor can have differing levels of expression of AR.

Biopsy of metastatic tumors in a patient to determine AR species is not feasible. Thus it is essential to develop approaches to detect the expression of all AR species for the molecular classification of tumors based on the level and extent of expression of AR splice variants to identify patients with potentially aggressive disease and poor prognosis, or to identify patients that will not respond to hormone therapies that target the AR LBD. Accordingly, certain embodiments of the present invention provide an AR NTD-targeted molecular imaging probe (e.g., compound of formula I) which can be used to monitor response to therapy and provide insight into the role of AR in resistance mechanisms.

Currently the approach to image AR in prostate cancer uses positron emission tomography (PET) with 16p-[ ^,8 F]-fluoro-5a dihydrotestosterone ( ¹⁸ F-FDHT) that binds to AR LBD. Unfortunately this imaging agent cannot detect splice variants lacking LBD. In some embodiments, the invention employs sequential imaging with ¹⁸ F -FDHT to detect full- length AR and positron emitting probes to specifically detect the AR NTD which would be the sum of both full-length AR and variant AR. Together these data reveal patients with tumors that express variant AR (NTD of variant plus fiill-length AR detected with NTD isotope minus full-length AR detected with ¹⁸ F -FDHT). By using sequential imaging, a discordant distribution or discordant level of uptake between ¹⁸ F -FDHT and a radiolabeled compound of this invention indicates the presence of overexpression of splice variants lacking the LBD.

Accordingly, certain embodiments of the present invention are directed to compounds that bind to the AR NTD and are useful for imaging of tumors with splice variants using PET. In one embodiment, the present disclosure provides an ¹⁸ F-labelled compound having a structure of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof wherein:

R ¹ is H, F or ¹⁸ F;

R ² is H or F; R ³ and R ⁴ are each independently F, ¹⁸ F or C ₁ -C ₅ alkyl;

Z is, at each occurrence, independently -0-, -S-, -SO ₂ -, -CH ₂ -, or -C(Y)(Q)-;

Q is H or F

is CH ₂ F, CH ₂ ^I8 F; C ₁ -C ₅ alkyl optionally substituted with F or ¹⁸ F, CH ₂ OH or

G is a moiety from Table I;

Y is H F, ^I8 F, OH or OG; and

n is an integer from 0 to 15;

wherein at least one of R ¹ , R ³ , R ⁴ , or Y is ¹⁸ F or X is CH ₂ ^I8 F or a C ₁ -C ₅ alkyl substituted with at least one ¹⁸ F moiety.

In another embodiment, the compound has one of the following structures (la) or (lb):

R ¹ is F. In other embodiments, R ¹ is . ¹⁸ F In any of the foregoing embodiments, R ² is H, and in other embodiments of any of the foregoing embodiments, Z is -C(Y)(Q)-. In some embodiments R ¹ is H and R ² is H. In still other embodiments of any of the foregoing n is 1.

In any of the foregoing embodiments, Y is F. In other embodiments, Y is ¹⁸ F. In other embodiments, Y is H. In other embodiments, Y is OH.

In any of the foregoing embodiments, Q is F or in other embodiments Q is H.

In some other embodiments of any of the foregoing embodiments, X is CH ₂ ¹⁸ F.

In some other embodiments of the compound of structure (I), the compound has one of the following structures (Ig); (Hi), (li) or (Ij):

In still other embodiments of any of the foregoing compounds of structure (Ig), (Ilh), (li) or (Ij), R ¹ is H, and in other embodiments, R ¹ is F. In other embodiments, R ¹ is ^ts F.

In some embodiments of any of the forgoing compounds of structure (Ig), (Ilh), (li) or (Ij), R ² is H. In some embodiments R ¹ is H and R ² is H.

In other embodiments of any of the forgoing compounds of structure (Ig), (Ilh), (li) or (Ij), Y is OH. In other embodiments, Y is H. In other embodiments, Y is F. In other embodiments, Y is ¹⁸ F.

In other embodiments of any of the forgoing compounds of structure (Ig), (Ilh), (li) or (Ij), Q is H. In other embodiments, Q is F. In other embodiments of any of the forgoing compounds of structure (Ig), (Ilh), (Ii) or (Ij), X is C ₁ -C ₅ alkyl optionally substituted with a ¹⁸ F moiety.

In other embodiments of any of the forgoing compounds of structure (Ig), (Ilh), (Ii) or (Ij), X is C ₁ -C ₅ alkyl substituted with a ¹⁸ F moiety. For example, in some embodiments, X is unsubstituted C ₁ -C ₅ alkyl. In other embodiments, X is methyl, ethyl, n-propyl, isopropyl, n- butyl or propargyl. In certain embodiments, the ^l8 F moiety, when present, is at a terminal position of the C ₁ -C ₅ alkyl.

In other embodiments of the compound of structure (I), the compound has one of the following structures (Ik); (II), (Im) or (In):

In still other embodiments of any of the foregoing compounds of structure (Ik); ai). (Im) or (In), R ¹ is H, and in other embodiments, R ¹ is F. In other embodiments, R ¹ is ¹⁸ F.

In other embodiments of the compound of structure (Ik); (Im) or (In), R ² is H. In some embodiments R ¹ is H and R ² is H.

In other embodiments of the compound of structure ak); (II), (Im) or (In), Y is OH. In other embodiments, Y is H. In other embodiments, Y is F. In other embodiments, Y is ¹⁸ F.

In other embodiments of the compound of structure (Ik); (II), (Im) or (In), Q is H. In other embodiments, Q is F.

In other embodiments of the compound of structure (Ik); (II). (Im) or (In), X is C ₁ -C ₅ alkyl optionally substituted with a ¹⁸ F moiety. For example in some embodiments, X is C ₁ - C ₅ alkyl substituted with a ¹⁸ F moiety. In other embodiments, X is unsubstituted C ₁ -C ₅ alkyl. In some embodiments, X is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl. In certain embodiments, the ¹⁸ F moiety, when present, is at a terminal position of the C ₁ -C ₅ alkyl.

In other embodiments of the compound of structure (I), the compound has one of the following structures (lo) or (Ip):

(Ip)

In still other embodiments of any of the foregoing compounds of structure (lo) or (Ip), R ¹ is H, and in other embodiments, R ¹ is F. In other embodiments, R ¹ is ¹⁸ F.

In other embodiments of the compound of structure (lo) or (Ip), R ² is H. In other embodiments, R ¹ is H and R ² is H.

In other embodiments of the compound of structure (lo) or (Ip), X is C ₁ -C ₅ alkyl optionally substituted with a ¹⁸ F moiety. For example in some embodiments, X is C ₁ -C ₅ alkyl substituted with a ¹⁸ F moiety. In other embodiments, X is unsubstituted C ₁ -C ₅ alkyl. In some other embodiments, X is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl. In certain embodiments, the ¹⁸ F moiety, when present, is at a terminal position of the C ₁ -C ₅ alkyl-

In some embodiments of any of the forgoing embodiments, at least one of R ³ or R ⁴ is methyl, and in some other embodiments each of R ³ and R ⁴ is methyl. In other embodiments, at least one of R ³ or R ⁴ is F, and in some other embodiments each of R ³ and R ⁴ is F.

embodiments of any of the forgoing embodiments, G is or In one embodiment of the compound of structure (I), the compound has one of the following structures:

or a pharmaceutically acceptable salt or stereoisomer thereof.

In another embodiment, the present disclosure provides a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable carrier.

In another embodiment, the present disclosure provides a method of imaging cancer, the method comprising administering the foregoing pharmaceutical composition of to a subject and detecting the presence or absence of cancer by use of positron emission tomography.

In certain embodiments, the method identifies the presence or absence of a tumor. For example, some embodiments the method identifies the location of a tumor. In certain embodiments, the cancer is prostate cancer, for example, castration resistant prostate cancer. In other embodiments, the prostate cancer is androgen-dependent prostate cancer.

In some embodiments, the method detects the presence of splice variants. In other embodiments the method detects the presence or overexpression of splice variants lacking the ligand binding domain. For example, the method may include sequential imaging with ¹⁸ F- FDHT and a compound of the invention and a discordant distribution or discordant level of uptake between ^l8 F-FDHT and the compound of the invention indicates the presence or overexpression of splice variants lacking the ligand binding domain.

In other embodiments, the compounds of the invention are used in PET methods to monitor a patient's response to therapy. In other embodiments, the methods comprise use of a compound of the invention to detect the AR NTD.

In some embodiments, the present invention is directed to compounds useful for preparation of a compound of Formula I. For example, in some embodiments, the disclosure provides a compound having a structure of Formula II:

or a salt or stereoisomer thereof, wherein:

R ⁶ is H or F;

R ⁷ and R ⁸ are each independently F, or C ₁ -C ₅ alkyl;

R ⁹ is CF3, optionally substituted C ₁ -C ₆ alkyl or optionally substituted aryl;

P is an alcohol protecting group;

Z ² is, at each occurrence, independently

alkyl optionally substituted with

G ² is a moiety from Table I;

n is an integer from 0 to 15,

wherein at least one of

CH ₂ I or combinations thereof.

In some embodiments, at least one of

combinations thereof.

In some embodiments of the compound of structure (II), the compound has one of the following structures (IIa) or (lIb):

In any of the foregoing embodiments of the compound of structure (II), R ⁵ is H. In other embodiments, R ⁵ is F. In other embodiments,

In any of the foregoing embodiments of the compound of structure (II), R ⁶ is H. In some embodiments, R ⁵ is H and R ⁶ is H. In some other embodiments of any of the foregoing embodiments of the compound of structure

In any of the foregoing embodiments of the compound of structure (II), n is 1.

In any of the foregoing embodiments of the compound of structure (II), Y ² is F. In other embodiments, Y ² is I. In some other embodiments, Y ² is -OS0 ₂ R ⁹ . In other embodiments, Y ² is H, and in other embodiments,Y ² is OH.

In other embodiments, Q ² is F. In other embodiments, Q ² is H.

In other embodiments, X ² is CH ₂ F. In other embodiments, X ² is CH ₂ I. In some other embodiments,

In other embodiments of the compound of structure (II), the compound has one of the following structures (fig); (lib), (IIi) or (Ilj):

In some embodiments of the compound of structure (Eg); (Ilh), (Ili) or (Ilj), R ⁵ is H. In other embodiments, R ⁵ is F. In other embodiments, R ⁵ is I. In other embodiments, R ⁵ is -

In any of the foregoing embodiments of the compound of structure (Ilg); (Ilh), (Ili) or (Ilj), R ⁶ is H. In some embodiments, R ⁵ is H and R ⁶ is H.

In any of the foregoing embodiments of the compound of structure (Ilg); (Ilh), (IIi) or (Ilj), Y ² is OH. In other embodiments, Y ² is H. In other embodiments, Y ² is F. In other embodiments, Y ² is I, In other embodiments,

In any of the foregoing embodiments of the compound of structure (Eg); (Ilh), (IIί) or (IIj), Q ² is H, In other embodiments, Q ² is F.

In any of the foregoing embodiments of the compound of structure (Ilg); (Ilh), (Ili) or (Ilj), X ² is CH ₂ I. In other embodiments In other embodiments, X ² is

C ₁ -C ₅ alkyl optionally substituted with F. For example, in some embodiments, X ² is C ₁ -C ₅ alkyl substituted with F. In other embodiments, X ² is unsubstituted C ₁ -C ₅ alkyl. In other embodiments, X ² is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl. In certain embodiments, the F moiety, when present, is at a terminal position of the C ₁ -C ₅ alkyl.

In some embodiments of the compound of structure (II), the compound has one of the following structures (Ilk); (II1), (Ilm) or (Iln):

(Iln)

In some embodiments of the compound of structure (Ilk); (III), (Ilm) or (Iln), R ⁵ is H.

In other embodiments, R ⁵ is F. In other embodiments, R ⁵ is I. In other embodiments, R ⁵ is - OS0 ² R ₉ .

In any of the foregoing embodiments of the compound of structure (Ilk); (III), (Ilm) or (IIη), R ⁶ is H. In some embodiments, R ⁵ is H and R ⁶ is H.

In any of the foregoing embodiments of the compound of structure (Ilk); (II1), (Ilm) or (Iln), Y ² is OH. In other embodiments, Y ² is H. In other embodiments, Y ² is F. In other embodiments, Y ² is I. In other embodiments, Y

In any of the foregoing embodiments of the compound of structure (Ilk); (II1), (Em) or (IIη), Q ² is H. In other embodiments, Q ² is F.

In any of the foregoing embodiments of the compound of structure (Tlk); (II1), (Em) or (IIn), X ² is CH ₂ I. In other embodiments, X ² is -CH ₂ OSO2R ⁹ . In other embodiments, X ² is C ₁ -C ₅ alkyl optionally substituted with F. For example, in some embodiments X ² is C ₁ -C ₅ alkyl substituted with F. In other embodiments X ² is unsubstituted C ₁ -C ₅ alkyl. In other embodiments, X ² is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl. In other embodiments, the F moiety, when present, is at a terminal position of the C ₁ -C ₅ alkyl.

In some other embodiments of the compound of structure (II), the compound has one of the following structures (IIo) or (IIp) :

In some embodiments of the compound of structure (IIο) or (lip), R ⁵ is H. In other embodiments, R ⁵ is F. In other embodiments, R ⁵ is I. In other embodiments, R ⁵ is -OS0 ² Rg.

In any of the foregoing embodiments of the compound of structure (IIo) or (IIp), R ⁶ is

H. In some embodiments, R ⁵ is H and R ⁶ is H.

In any of the foregoing embodiments of the compound of structure (IIο) or (lip), X ² is CH ₂ I. In other embodiments, X ² is -CH ₂ OSO ₂ R ⁹ In other embodiments, X ² is C ₁ -C ₅ alkyl optionally substituted with F. In other embodiments, X ² is C ₁ -C ₅ alkyl substituted with F. In other embodiments, X ² is unsubstituted C ₁ -C ₅ alkyl. In other embodiments, X ² is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl. In other embodiments, the F moiety, when present, is at a terminal position of the C ₁ -C ₅ alkyl.

In any of the foregoing embodiments of the compound of structure (II), at least one of R ⁷ or R ⁸ is methyl. In other embodiments, each of R ⁷ and R ⁸ is methyl. In other embodiments, at least one of R ⁷ or R ⁸ is F. In other embodiments, each of R ⁷ and R ⁸ is F.

In any of the foregoing embodiments of the compound of structure (II), R ⁹ is methyl or CF3. In other embodiments, R ⁹ is phenyl optionally substituted with methyl or nitro. In other embodiments, R ⁹ is phenyl, p-methylphenyl or m-nitrophenyl. embodiments of the compound of structure (II), G is

In some embodiments of the compound of structure (II), the compound has one of the following structures:

or a pharmaceutically acceptable salt or stereoisomer thereof.

In other embodiments of the foregoing, R ⁹ is methyl or CF3. In other embodiments, R ⁹ is phenyl optionally substituted with methyl or nitro. In other embodiments, R ⁹ is phenyl, p-methylphenyl or m-nitrophenyl.

In another embodiment, the present disclosure provides a method for preparing a compound of structure (I), the method comprising reacting a compound of structure (II) with a reagent comprising ¹⁸ F. In other embodiments, the reagent is [K ⁺ 2,2,2-cryptand] ¹⁸ F- or n- Bu ₄ N ⁺¹⁸ F".

Each R ³ may independently be C ₁ -C ₅ alkyl. Each R ³ may independently be C ₁ -C ₄ alkyl. Each R ³ may independently be C ₁ -C ₃ alkyl. Each R ³ may independently be C ₁ -C ₂ alkyl.

Each R ³ may independently be methyl. Each R ³ may independently be C ₂ alkyl. Each R ³ may independently be C ₃ alkyl. Each R ³ may independently be C ₄ alkyl. Each R ³ may independently be C ₅ alkyl. Each R ³ may independently be F.

Each R ⁴ may independently be C1-C5 alkyl. Each R ⁴ may independently be C ₁ -C ₄ alkyl. Each R ⁴ may independently be C ₁ -C ₃ alkyl. Each R ⁴ may independently be C ₁ -C ₂ alkyl.

Each R ⁴ may independently be methyl. Each R ⁴ may independently be C ₂ alkyl. Each R ⁴ may independently be C ₃ alkyl. Each R ⁴ may independently be C ₄ alkyl. Each R ⁴ may independently be C ₅ alkyl. Each R ⁴ may independently be F.

Each R ⁷ may independently be C ₁ -C ₅ alkyl. Each R ⁷ may independently be C ₁ -C ₄ alkyl. Each R ⁷ may independently be C ₁ -C ₃ alkyl. Each R ⁷ may independently be C ₁ -C ₂ alkyl.

Each R ⁷ may independently be methyl. Each R ⁷ may independently be C ₂ alkyl. Each R ⁷ may independently be C ₃ alkyl. Each R ⁷ may independently be C ₄ alkyl. Each R ⁷ may independently be C ₅ alkyl. Each R ⁷ may independently be F.

Each R ⁸ may independently be C ₁ -C ₅ alkyl. Each R ⁸ may independently be C ₁ -C ₄ alkyl. Each R ⁸ may independently be C ₁ -C ₃ alkyl. Each R ⁸ may independently be C ₁ -C ₂ alkyl.

Each R ⁸ may independently be methyl. Each R ⁸ may independently be C ₂ alkyl. Each R ⁸ may independently be C ₃ alkyl. Each R ⁸ may independently be C ₄ alkyl. Each R ⁸ may independently be C ₅ alkyl. Each R ⁸ may independently be F.

In some embodiments, compounds of structure I or II which result in unstable structures and/or unsatisfied valences are not included within the scope of the invention.

In another embodiment, the present disclosure provides the use of any one of the foregoing compounds of Formula (I) for imaging cancer. For example in some embodiments, the imaging is in a human patient.

The compounds described herein are meant to include all racemic mixtures and all individual enantiomers or combinations thereof, whether or not they are specifically depicted herein. Alternatively, one or more of the OH groups on the above compounds may be substituted to replace the H with a moiety selected from Table 1 (i.e., to form a OY moiety).

In accordance with another embodiment, there is provided a use of the compounds of Formula (I) as described anywhere herein for preparation of a medicament for imaging cancer (e.g., tumors), for example prostate cancer.

The imaging may be in a mammalian cell. The imaging may be in a mammal. The mammal may be a human.

Alternatively, the compounds may be administered to a mammal for imaging purposes. The administering and imaging may be to a mammal in need of diagnosis of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy (e.g., Kennedy's disease), and age-related macular degeneration. The mammalian cell may be a human cell. The imaging may be for imaging splice variants.

Table 1. Amino Acid, Polyethylene Glycol, and Phosphate Based Moieties

Moieties from TABLE 1 may be, for example, and without limitation, subdivided into three groups: 1) amino acid based moieties; 2) polyethylene glycol based moieties; and 3) phosphate based moieties. In the Moieties Table 1 above, the first four moieties are amino acid based moieties, the fifth and sixth are polyethylene glycol based moieties and the remaining moieties are phosphate based moieties.

The amino acid side chains of naturally occurring amino acids (as often denoted herein using "(aa)") are well known to a person of skill in the art and may be found in a variety of text books such as "Molecular Cell Biology" by James Darnell et al. Third Edition, published by Scientific American Books in 1995. Often the naturally occurring amino acids are represented by the formula (NH ₂ )C(COOH)(H)(R), where the chemical groups in brackets are each bonded to the carbon not in brackets. R represents the side chains in this particular formula.

Those skilled in the art will appreciate that the point of covalent attachment of the moiety to the compounds as described herein may be, for example, and without limitation, cleaved under specified conditions. Specified conditions may include, for example, and without limitation, in vivo enzymatic or non-enzymatic means. Cleavage of the moiety may occur, for example, and without limitation, spontaneously, or it may be catalyzed, induced by another agent, or a change in a physical parameter or environmental parameter, for example, an enzyme, light, acid, temperature or pH. The moiety may be, for example, and without limitation, a protecting group that acts to mask a functional group, a group that acts as a substrate for one or more active or passive transport mechanisms, or a group that acts to impart or enhance a property of the compound, for example, solubility, bioavailability or localization.

In other particular embodiments of the compounds as described anywhere herein, the following compounds in Table 2 are provided. As noted above, such compounds find utility for use in imaging cancer (e.g., tumors), for example prostate cancer.

Table 2. Representative ¹⁸ F Compounds



Prodrugs are also included within the scope of the present disclosure. For example, in one embodiment the hydrogen atom of one or more hydroxyl groups of any of the compounds of Formula I may be replaced with a moiety from Table 1 (i.e., to form a OY moiety). Non-limiting examples of such prodrugs include glycine esters and salts thereof as shown below.

In some embodiments, the compounds as described herein or acceptable salts thereof may be used for imaging and diagnosis of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. In some embodiments, the compounds as described herein or acceptable salts thereof above may be used in the preparation of a medicament or a composition for imaging cancer in a subject in need of such imaging (for example for diagnosis and/or location of tumors).

Some aspects of this invention make use of compositions comprising a compound described herein and a pharmaceutically acceptable excipients or carrier. In some 5 embodiments, the prostate cancer is castration-resistant prostate cancer (also referred to as hormone refractory, androgen-independent, androgen deprivation resistant, androgen ablation resistant, androgen depletion-independent, castration-recurrent, anti-androgen-recurrent). In some embodiments the prostate cancer is androgen-dependent or androgen-sensitive. Methods of imaging any of the indications described herein are also provided. Such methods

10 may include administering a compound as described herein or a composition of a compound as described herein, or an effective amount of a compound as described herein or composition of a compound as described herein to a subject in need thereof.

In an exemplary embodiment for diagnosing or identifying tumor or metastatic disease, a dose of the disclosed compounds in solution (typically 5 to 10 millicuries or 200 to

15 400 MBq) is typically injected rapidly into a saline drip running into a vein, in a patient Then, the patient is placed in the PET scanner for a series of one or more scans which may take from 20 minutes to as long as an hour (often, only about one quarter of the body length may be imaged at a time). Methods for PET scanning are well known in the art

Compounds as described herein include all stereoisomers. Accordingly, the 0 compounds include racemic mixtures, enantiomers and diastereomers of any of the compounds described herein.

Compounds as described herein may be in the free form or in the form of a salt thereof. In some embodiments, compounds as described herein may be in the form of a pharmaceutically acceptable salt which are known in the art (Berge et al., J. Pharm. Sci. 5 1977, 66, 1). Pharmaceutically acceptable salt as used herein includes, for example, salts that have the desired pharmacological activity of the parent compound (salts which retain the biological effectiveness and/or properties of the parent compound and which are not biologically and/or otherwise undesirable). Compounds as described herein having one or more functional groups capable of forming a salt may be, for example, formed as a0 pharmaceutically acceptable salt. Compounds containing one or more basic functional groups may be capable of forming a pharmaceutically acceptable salt with, for example, a pharmaceutically acceptable organic or inorganic acid. Pharmaceutically acceptable salts may be derived from, for example, and without limitation, acetic acid, adipic acid, alginic acid, aspartic acid, ascorbic acid, benzoic acid, benzenesulfonic acid, butyric acid, cinnamic acid, citric acid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid, diethylacetic acid, digluconic acid, dodecylsulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid, heptanoic acid, hexanoic acid, hydrochloric acid, hydrobromic acid, hydriodic acid, 2- hydroxyethanesulfonic acid, isonicotinic acid, lactic acid, malic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napthalenesulfonic acid, naphthalenedisulphonic acid, p-to!uenesulfonic acid, nicotinic acid, nitric acid, oxalic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, phosphoric acid, picric acid, pimelic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, succinic acid, sulfuric acid, sulfamic acid, tartaric acid, thiocyanic acid or undecanoic acid. Compounds containing one or more acidic functional groups may be capable of forming pharmaceutically acceptable salts with a pharmaceutically acceptable base, for example, and without limitation, inorganic bases based on alkaline metals or alkaline earth metals or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, quaternary amine compounds, substituted amines, naturally occurring substituted amines, cyclic amines or basic ion- exchange resins. Pharmaceutically acceptable salts may be derived from, for example, and without limitation, a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation such as ammonium, sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese or aluminum, ammonia, benzathine, meglumine, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanoI, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, procaine, N-ethylpiperidine, theobromine, tetramethyiammonium compounds, tetraethylammonium compounds, pyridine, N,N- dimethylaniline, N-methylpiperidine, morpholine, N-methylmorpholine, N-ethylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, Ν,Ν'- dibenzylethylenediamine or polyamine resins. In some embodiments, compounds as described herein may contain both acidic and basic groups and may be in the form of inner salts or zwitterions, for example, and without limitation, betaines. Salts as described herein may be prepared by conventional processes known to a person skilled in the art, for example, and without limitation, by reacting the free form with an organic acid or inorganic acid or base, or by anion exchange or cation exchange from other salts. Those skilled in the art will appreciate that preparation of salts may occur in situ during isolation and purification of the compounds or preparation of salts may occur by separately reacting an isolated and purified compound.

In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, polymorphs, isomeric forms) as described herein may be in the solvent addition form, for example, solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent in physical association the compound or salt thereof. The solvent may be, for example, and without limitation, a pharmaceutically acceptable solvent. For example, hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol.

In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, solvates, isomeric forms) as described herein may include crystalline and amorphous forms, for example, polymorphs, pseudopolymorphs, conformational polymorphs, amorphous forms, or a combination thereof. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and/or solubility. Those skilled in the art will appreciate that various factors including recrystallization solvent, rate of crystallization and storage temperature may cause a single crystal form to dominate.

In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, solvates, polymorphs) as described herein include isomers such as geometrical isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, individual enantiomers, individual diastereomers, racemates, diastereomeric mixtures and combinations thereof, and are not limited by the description of the formula illustrated for the sake of convenience.

In some embodiments, pharmaceutical compositions in accordance with this invention may comprise a salt of such a compound, preferably a pharmaceutically or physiologically acceptable salt. Pharmaceutical preparations will typically comprise one or more carriers, excipients or diluents acceptable for the mode of administration of the preparation, be it by injection, inhalation, topical administration, lavage, or other modes suitable for the selected treatment. Suitable carriers, excipients or diluents are those known in the art for use in such modes of administration.

Suitable pharmaceutical compositions may be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner. For parenteral administration, a compound may be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non-water soluble compounds such as those used for vitamin K. For enteral administration, the compound may be administered in a tablet, capsule or dissolved in liquid form. The tablet or capsule may be enteric coated, or in a formulation for sustained release. Many suitable formulations are 5 known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, pastes, gels, hydrogels, or solutions which can be used topically or locally to administer a compound. A sustained release patch or implant may be employed to provide release over a prolonged period of time. Many techniques known to one of skill in the art are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro,

10 20 ^th ed., Lippencott Williams & Wilkins, (2000). Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral

15 delivery systems for modulatory compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

20 Compounds or pharmaceutical compositions in accordance with this invention or for use in this invention may be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, etc. Also, implants may be devised which are intended to contain and release such compounds or compositions. An example would be an implant made of a polymeric material adapted to release the compound over a period of time.

5 An "effective amount" of a pharmaceutical composition according to the invention includes a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduced tumor size, increased life span or increased life expectancy. A therapeutically effective amount of a 0 compound may vary according to factors such as the disease state, age, sex, and weight of the subject and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as smaller tumors, increased life span, increased life expectancy or prevention of the progression of prostate cancer to an androgen-independent form. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.

It is to be noted that dosage values may vary with the exact imaging protocol. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners. The amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens may be adjusted to provide the optimum imaging result. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the imaging results. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.

In general, compounds of the invention should be used without causing substantial toxicity. Toxicity of the compounds of the invention can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e.,, the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population). In some circumstances however, such as in severe disease conditions, it may be necessary to administer substantial excesses of the compositions. Some compounds of this invention may be toxic at some concentrations. Titration studies may be used to determine toxic and non-toxic concentrations. Toxicity may be evaluated by examining a particular compound's or composition's specificity across cell lines using PC ₃ cells as a negative control that do not express functional AR. Animal studies may be used to provide an indication if the compound has any effects on other tissues. Systemic therapy that targets the AR will not likely cause major problems to other tissues since antiandrogens and androgen insensitivity syndrome are not fatal.

Compounds as described herein may be administered to a subject. As used herein, a "subject" may be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like. The subject may be suspected of having or at risk for having a cancer, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, or suspected of having or at risk for having acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration. Diagnostic methods for various cancers, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, and diagnostic methods for acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration and the clinical delineation of cancer, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, diagnoses and the clinical delineation of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration are known to those of ordinary skill in the art.

Compounds for use in the present invention may be obtained from medical sources or modified using known methodologies from naturally occurring compounds. In addition, methods of preparing or synthesizing compounds of the present invention will be understood by a person of skill in the art having reference to known chemical synthesis principles. For example, Auzou et al 1974 European Journal of Medicinal Chemistry 9(5), 548-554 describes suitable synthetic procedures that may be considered and suitably adapted for preparing compounds of any one of the Formula I to XXI as set out above. Other references that may be helpful include: Debasish Das, Jyh-Fu Lee and Soofin Cheng "Sulfonic acid functionalized mesoporous MCM-41 silica as a convenient catalyst for Bisphenol-A synthesis" Chemical Communications, (2001) 2178-2179; US Patent 2571217 Davis, Orris L.; Knight, Horace S.; Skinner, John R. (Shell Development Co.) "Halohydrin ethers of phenols." (1951); and Rokicki, G.; Pawlicki, J.; Kuran, W. "Reactions of 4-chloromethyl-l,3-dioxoIan-2-one with phenols as a new route to polyols and cyclic carbonates." Journal fuer Praktische Chemie (Leipzig) (1985) 327, 718-722.

For example, compounds of the present invention may be prepared with reference to the following General Reaction Scheme I: General Reaction Scheme I

Referring to General Reaction Scheme I, compounds of structure A can be prepared according to General Reaction Scheme II (below) and/or according to methods known in the art and/or disclosed in copending PCT Application Nos. PCT/CA2009/000902; PCT/CA2011/000021 and PCT/CA2011/000019 and in U.S. Provisional Application. Nos. 61/473,676 and 61/525,643, each of which are hereby incorporated by reference in their entireties. Compounds of structure A can be converted to compounds comprising an appropriate leaving group (e.g., compound B) by treatment with any variety of reagents, for example mesyl chloride, tosyl chloride or triflic anhydride. The ¹⁸ F moiety can then be incorporated into b via any number of methods, for example treatment with ΓΚ ⁺ 2,2,2- cryptand] ¹⁸ F or n-Bu ₄ N ⁺ l 8F ^" (see e.g., Bioorg. Med. Chem. 17, 7441-7448, 2009 and J.Med. Chem. 33, 2430-2437, 1990, each of which are hereby incorporated by reference in their entireties). Other methods for ^l8 F incorporation can be determined by one skilled in the art. General Reaction Scheme II

General Reaction Scheme II illustrates an exemplary procedure for preparing compounds which can be fluorinated according to General Reaction Scheme I. Referring to General reaction Scheme II, compounds of structure D can be purchased from commercial sources or prepared according to methods known in the art. Reaction of D with an appropriately epoxide under basic conditions, yields compounds of structure E. Optically pure or racemic epoxides may be employed to yield the desired stereochemistry. Reaction of E with an appropriately substituted chloropropane, for example a bromo-chloropropane, results in compounds of structure F. Compounds of structure F can then be fluorinated with ¹⁸ F according to the procedures described in General Reaction Scheme I.

In addition to ¹⁸ ,F various methods for incorporation of fluorine (i.e., not ^I8 F) into the compounds of the disclosure are available. Methods for such fluorination are well known. For example, in one embodiment a fluorine atom is introduced by treatment with diethylaminosulfurtrifluoride (DAST) or Xtalfluor-E or M (see J. Org. Chem. 2010, 75, 3401-341 1, which is hereby incorporated by reference in its entirety). In other embodiments, the hydroxyl moiety in G may be converted to an appropriate leaving group, for example by reaction with tosyl chloride or mesyl anhydride, followed by reaction with [K ⁺ /2,2,2- cryptand]F ^* or tetrabutylammoniura fluoride. Other methods for fluorination of G are known to those of skill in the art. For descriptions of fluorination procedures see J, Org. Chem. 2010, 75, 3401-3411, Bioorg. Med. Chem. 2009, 17, 7441-7448, and J. Med. Chem. 1990, 33, 2430-2437, each of which is hereby incorporated by reference in its entirety.

One skilled in the art will recognize that variations to the order of the steps and reagents discussed in reference to the above General Synthetic Schemes I and II are possible. Further, fluorine atoms may be introduced via any number of reagents, and fluorination is not limited to those methods depicted or described above. Methods for such fluorination are well known in the art. Finally, prodrugs of Formula I can be prepared by functionalizing a free hydroxy I in structure in any of the above compounds. Methods for such functionalization are well-known in the art, for example reaction with an acid chloride analogue of a moiety from Table 1 or any other suitable reagent. Methodologies for preparation of compounds of Formula I are described in more detail in the following non-limiting exemplary schemes.

In addition, protecting group strategies may be employed for preparation of the compounds disclosed herein. Such strategies are well known to those of skill in the art. Exemplary protecting groups and related strategies are disclosed in Greene's Protective Groups in Organic Synthesis, Wiley-Interscience; 4 edition (October 30, 2006), which is hereby incorporated by reference in its entirety. In certain embodiments, a protecting group is used to mask an alcohol moiety while performing other chemical transformations. After removal of the protecting group, the free hydroxyl is obtained. Such protecting groups and strategies are well known in the art.

Exemplary compounds useful as intermediates for preparation of the compounds of structure (I) are provided below in Table 3, wherein L represents a mesyl, tosyl, or triflate group.

Table 3. Representative Compounds of Structure (II)

55 EXAMPLES

All non-aqueous reactions are performed in flame-dried round bottomed flasks. The flasks are fitted with rubber septa and reactions are conducted under a positive pressure of argon unless otherwise specified. Stainless steel syringes are used to transfer air- and moisture-sensitive liquids. Flash column chromatography is performed as described by Still et al. (Still, W. C; Kahn, M.; Mitra, A. J. Org. Chew. 1978, 43, 2923) using 230-400 mesh silica gel. Thin-layer chromatography is performed using aluminum plates pre-coated with 0.25 mm 230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin- layer chromatography plates are visualized by exposure to ultraviolet light and a "Seebach" staining solution (700 mL water, 10.5 g Cerium (TV) sulphate tetrahydrate, 15.0 g molybdate phosphoric acid, 17.5 g sulphuric acid) followed by heating (~1 min) with a heating gun (-250 °C). Organic solutions are concentrated on BOchi R-114 rotatory evaporators at reduced pressure (15-30 torr, house vacuum) at 25-40 °C.

Commercial regents and solvents are used as received. All solvents used for extraction and chromatography are HPLC grade. Normal-phase Si gel Sep paks™ are purchased from waters, Inc. Thin-layer chromatography plates are Kieselgel 6OF254. All synthetic reagents are purchased from Sigma Aldrich and Fisher Scientific Canada.

EXAMPLE 1

^{I 8} F is produced using an ACSI TR-19 cyclotron at the British Columbia Cancer Agency from H ₂ ¹⁸ 0 via the ¹⁸ 0(p,n) ¹⁸ F nuclear reaction. After bombardment, the H ₂ ^I8 0 (~ 2 mL) containing 160 - 450 mCi ^l8 F is passed through a QMA cartridge, and the ¹⁸ F retained on the cartridge is eluted out with a solution of K2CO3 (7 mg) and kryptofix (K222, 22 mg) in CH ₃ CN (0.3 mL) and water (0.3 mL) into a 4-mL reaction vial. The solution is evaporated at 120 °C, followed by two azeotropic distillations using 1 mL of CH ₃ CN.

Compound (A) is prepared according to the general procedures described above using protecting group strategies well known in the art. A solution of tetrahydropyran (THP) protected tosylate analogue (A) (2 mg) in DMSO (0.5 mL) is added, and the reaction vial is sealed and incubated at 100 °C for 20 min. Aqueous H2SO4 solution (0.5 N, 1 mL) is then added to remove the tetrahydropyranyl protecting groups. After another 5 min incubation at 100 °C, the reaction mixture is neutralized with 30% NaOAc aqueous solution (0.3 mL), and purified by HPLC under isocratic conditions (1:1 H2O /CH ₃ CN, 4.5 mL/min) on a Phenomenex Luna C-18 semi-preparative column (250 mm x 10 mm, 5 μm) monitored online for UV absorption at 220 nm. The HPLC elution fraction containing la (IR. = 18.7 min, see Figure 1A) is collected, diluted with water, and passed through a light tC ₁ 8 sep-pak cartridge. The trapped la on the cartridge is eluted out with DMSO (0.4 mL). For imaging studies, a fraction of the eluted DMSO solution is diluted with a 30% PEG solution to make a final la solution containing < 5% DMSO and with activity concentration at ~ 1.0 mCi/mL.

The final la compound is obtained in 20-50 % decay-corrected isolated yield, and with >98% radiochemical purity and high specificity activity (5-20Ci/μmοΙβ) suitable for imaging. A typical HPLC chromatogram is shown in Figure IB.

EXAMPLE 2

IMAGING STUDIES

Mature male mice are injected with compound la (lOOuCi) either with or without prior blocking using 50mg/kg body weight of an identical, non-radiolabeled compound. In mice, compound la is expected to distribute throughout the animal evenly within the first 5 minutes including the brain. Activity in the blood is expected to clear within 30 - 40 minutes with the majority of the tracer found in the region of the gut. Compound la is expected to be excreted via the liver rather than the kidney. Low activity is expected to be found in the bladder after 3 hours; bone and muscle uptake is also expected to be low. Scanning reveals that compound la targets androgen dependent tissue such as the seminal vesicles and prostate while in the blocked animal the levels are expected to remain constant. Neither the blocked or unblocked testes are expected to show this same trend.

Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes more than one such thing. Citation of references herein is not an admission that such references are prior art to the present invention. Any priority document(s) and all publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.