WO2013028791A1 - 18f compounds for cancer imaging and methods for their use - Google Patents

Abstract

Compounds having a structure of Formula I: or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1, R2, R3, R4, Z, X and n are as defined herein, and wherein the compound comprises at least one ¹⁸F moiety, are provided. Uses of such compounds for imaging diagnostics in cancer, including prostate cancer as well as methods and intermediates for preparing such compounds are also provided.

Description

¹⁸F COMPOUNDS FOR CANCER IMAGING AND METHODS FOR THEIR USE

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 61/526,227, filed August 22, 2011, which application is incorporated herein by reference in its entirety.

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

Technical Field

This invention relates to radiolabeled compounds, their uses and methods for imaging tumors, including prostate cancer tumors. In particular the invention relates to radioactive ¹⁸F 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, anti-androgen-recurrent).

Description of the Related Art

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 ScandJ. Urol 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; Estebanez-Perpina 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- 1 (AF l) 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. 21 A, 7777-7783; Sadar MD et al 1999 Endocr Relat Cancer. 6, 487-502; Ueda et al 2002 J. Biol. Chem. 211, 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-terminus 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 a useful research and treatment tool. In this regard, positron emission tomography (PET) is an often used imaging technique for noninvasive identification of tumors. In PET imaging, the distribution of a radioisotope {e.g., ¹⁸F) in the body can be determined. Thus incorporating ¹⁸F 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:

I or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R¹, R², R³, R⁴, Z, X and n are as defined herein, and wherein the compound comprises at least one ¹⁸F 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. BRIEF DESCRIPTION OF THE DRAWINGS

In the figures, identical reference numbers identify similar elements. The sizes and relative positions of elements in the figures are not necessarily drawn to scale and some of these elements are arbitrarily enlarged and positioned to improve figure legibility. Further, the particular shapes of the elements as drawn are not intended to convey any information regarding the actual shape of the particular elements, and have been solely selected for ease of recognition in the figures.

Figures 1A and IB are HPLC chromatograms showing crude and purified radiolabeled compound, respectively.

Figure 2 is a gel depicting binding of a representative compound to AF-1 in the AR NTD.

Figure 3 is a gel showing specific binding of a non-radiolabelled analogue to AR NTD.

Figure 4 presents imaging data for a representative compound.

Figure 5 is shows distribution of a representative radiolabeled compound in a mouse pre-treated with a non radiolabeled compound (left) and a mouse without pretreatment (right).

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" 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 Ci-C₆ alkyl and an alkyl comprising up to 5 carbon atoms is a Ci-C₅ alkyl. A Ci-C₅ alkyl includes C₅ alkyls, C₄ alkyls, C₃ alkyls, C₂ alkyls and Ci alkyl (i.e., methyl) and includes, for example, and without limitation, saturated C₁-C5 alkyl, C₂-C5 alkenyl and C₂-C5 alkynyl. Non-limiting examples of saturated C₁-C5 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 C₂-C₅ alkenyl include vinyl, allyl, isopropenyl, l-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 C₂-C5 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 Ci-C₆ alkyl includes all moieties described above for C₁-C5 alkyls but also includes C₆ alkyls.

"Aryl" means an aromatic carbocyclic moiety such as phenyl, naphthyl and the like. An aryl moiety may be optionally substituted, for example with C1-C6 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. "¹⁸F" refers to the radioactive isotope of fluorine having atomic mass 18. "F" or "¹⁹F" refers to the abundant, non radioactive fluorine isotope having atomic mass 19. The compounds of structure (I) comprise at least one ¹⁸F moiety. Throughout the present application, where structures depict a F moiety at a certain position it is meant that the F moiety at this position is enriched for ¹⁸F. In other words, the compounds contain more than the natural abundance of ¹⁸F at the indicated position(s). It is not required that the compounds comprise 100% ¹⁸F at the indicated positions, provided ¹⁸F is present in more than the natural abundance. Typically the ¹⁸F isotope is enriched to greater than 50%, greater than 60%, greater than 70%, greater than, 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 entity may be specified by inference.

For example, the compound CH₃-R , wherein R is H or " i " infers that when R is "XY", the point of attachment bond is the same bond as the bond by which R³ is depicted as being bonded to CH₃.

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 a 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-[¹⁸F]-fluoro-5a dihydrotestosterone (¹⁸F-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 ¹⁸F -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 full-length AR detected with NTD isotope minus full-length AR detected with ¹⁸F - FDHT). By using sequential imaging, a discordant distribution or discordant level of uptake between ¹⁸F -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 ¹⁸F- labelled compound having a structure of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

R¹ is F, ¹⁸F, OH or OG;

R² is H or F;

R³ and R⁴ are each independently F, F or C1-C5 alkyl;

Z is, at each occurrence, independently -0-, -S-, -S0₂-, -CH₂-, or

-C(Y)(Q>;

Q is H or F

X is CH₂F, CH₂ ¹⁸F; C C₅ alkyl optionally substituted with F or ¹⁸F, CH₂OH or CH₂OG;

G is a moiety from Table I;

Y is H F, ¹⁸F, OH or OG; and

n is an integer from 0 to 15;

wherein at least one of R¹, R³, R⁴, or Y is ¹⁸F or X is CH₂ ¹⁸F or a C C₅ alkyl substituted with at least one ¹⁸F moiety.

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

(la) (lb)

In any of the foregoing embodiments, the compound has one of the following structures (Ic), (Id), (Ie) or (If):

(Ic) (Id)

(Ie) (If)

In still other embodiments of any of the foregoing, R¹ is OH.

In any of the foregoing embodiments, R² is H, and in other embodiments of any of the foregoing embodiments, Z is -C(Y)(Q)-. In some embodiments R¹ is OH and R² 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 ¹⁸F. 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

CH₂ ¹⁸F.

In some other embodiments of the compound of structure (I), the compound has one of the followin structures (Ig); (Ih), (Ii) or (Ij):

(Ig) (Ih)

or

(Ii) (Ij)

In other embodiments of the foregoing, R¹ is OH. In some embodiments of any of the forgoing compounds of structure (Ig), (Ilh), (Ii) or (Ij), R² is H. In some embodiments R¹ is OH and R² is H.

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

In other embodiments of any of the forgoing compounds of structure (Ig), (Ilh), (Ii) 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 C₁-C5 alkyl optionally substituted with a ¹⁸F moiety.

In other embodiments of any of the forgoing compounds of structure (Ig), (Ilh), (Ii) or (Ij), X is C₁-C5 alkyl substituted with a ¹⁸F moiety. For example, in some embodiments, X is unsubstituted C₁-C5 alkyl. In other embodiments, X is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl. In certain embodiments, the ¹⁸F moiety, when present, is at a terminal position of the C₁-C5 alkyl.

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

(Im) (In)

In some embodiments of the foregoing, R¹ is OH.

In other embodiments of the compound of structure (Ik); (II), (Im) or (In), R² is H. In some embodiments R¹ is OH and R² is H. In other embodiments of the compound of structure (Ik); (II), (Im) or (In), Y is OH. In other embodiments, Y is H. In other embodiments, Y is F. In other embodiments, Y is ¹⁸F.

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 C₁-C5 alkyl optionally substituted with a ¹⁸F moiety. For example in some embodiments, X is C₁-C5 alkyl substituted with a ¹⁸F moiety. In other embodiments, X is unsubstituted C₁-C5 alkyl. In some embodiments, X is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl. In certain embodiments, the ¹⁸F moiety, when present, f s at a terminal position of the C₁-C5 alkyl.

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

(Io) (Ip)

In some embodiments of the foregoing, R¹ is OH.

In other embodiments of the compound of structure (Io) or (Ip), R² is H.

In other embodiments of the compound of structure (Io) or (Ip), X is C₁-C5 alkyl optionally substituted with a ¹⁸F moiety. For example in some

embodiments, X is C₁-C5 alkyl substituted with a ¹⁸F moiety. In other embodiments, X is unsubstituted C₁-C5 alkyl. In some other embodiments, X is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl. In certain embodiments, the ¹⁸F moiety, when present, is at a terminal position of the C₁-C5 alkyl.

In some embodiments of any of the forgoing embodiments, at least one of R³ or R⁴ is methyl, and in some other embodiments each of R³ and R⁴ is methyl. In other embodiments,at least one of R³ or R⁴ is F, and in some other embodiments each of R³ and R⁴ is F.

In some embodiments of any of the forgoing embodiments, G is

In some embodiments, Z is O. In other embodiments, Z is CH₂. In still other embodiments, each occurrence of Z is either O or CH₂, for example in some embodiments the compound comprise one or more ethylene glycol repeating units.

In some embodiments of any of the forgoing embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In other embodiments, n is 4. In other embodiments, n is 5. In other embodiments, n is 6. In other embodiments, n is 7. In other embodiments, n is 8. In other embodiments, n is 9. In other embodiments, n is 10. In other embodiments, n is 11. In other

embodiments, n is 12. In other embodiments, n is 13. In other embodiments, n is 14. In other embodiments, n is 15.

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 ligan binding domain. For example, the method may include sequential imaging with ¹⁸F-FDHT and a compound of the invention and a discordant distribution or discordant level of uptake between ¹⁸F-FDHT and the compound of the invention indicates the presence or overexpression of splice variants lacking the ligan 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:

II or a salt or stereoisomer thereof, wherein:

ft⁵ is F, OH, -OG², -OP, I or -OS0₂R⁹;

R⁶ is H or F;

R⁷ and R⁸ are each independently F, or C₁-C₅ alkyl;

R⁹ is CF₃, optionally substituted Ci-C₆ alkyl or optionally substituted aryl;

P is an alcohol protecting group;

Z² is, at each occurrence, independently -0-, -S-, -S0₂-, -CH₂-, or

-C(Y²)(Q²)-;

X² is CH₂F, CH₂I, C₁-C₅ alkyl optionally substituted with F, CH₂OH, CH₂OG², CH₂OP or -CH₂OS0₂R⁹;

G² is a moiety from Table I;

Q² is H or F

Y² is H, F, I, OH, -OG², -OP, or -OS0₂R⁹; and

n² is an integer from 0 to 15,

wherein at least one of R⁵ or Y is -OS0₂R⁹ or wherein X² is -CH₂OS0₂R⁹ or combinations thereof.

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

In any of the foregoing embodiments of the compound of structure (II), R⁵ is OH. In other embodiments, R⁵ is I. R⁵ is -OS0₂R⁹.

In any of the foregoing embodiments of the compound of structure (II), R⁶ is H. In some embodiments, R⁵ is OH and R⁶ is H.

In some other embodiments of any of the foregoing embodiments of the compound of structure (II), Z² is -C(Y²)(Q²)-.

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), Y² is F. In other embodiments,Y² is I. In some other embodiments, Y² is -OS0₂R⁹. In other embodiments,Y² is H, and in other embodiments,Y² is OH.

In other embodiments, Q² is F. In other embodiments, Q² is H. In other embodiments, X² is CH₂F. In other embodiments, X² is CH₂I. In some other embodiments, X² is -CH₂OS0₂R⁹.

In other embodiments of the compound of structure (II), the compound has one of the following structures (Ilg); (Ilh), (Hi) or (Iij):

(Hi) (iij)

In some embodiments of the compound of structure (Ilg); (Ilh), (Hi) or (Iij), R⁵ is OH. In other embodiments, R⁵ is I. In other embodiments, R⁵ is -OS0²Rg.

In any of the foregoing embodiments of the compound of structure (Ilg); (Ilh), (Hi) or (Iij), R⁶ is H. In some embodiments, R⁵ is OH and R⁶ is H.

In any of the foregoing embodiments of the compound of structure (Ilg); (Ilh), (Hi) or (Iij), Y² is OH. In other embodiments, Y² is H. In other embodiments, Y² is F. In other embodiments, Y² is I. In other embodiments, Y² is -OSO₂R₉.

In any of the foregoing embodiments of the compound of structure (Ilg); (Ilh), (Hi) or (Iij), Q² is H. In other embodiments, Q² is F.

In any of the foregoing embodiments of the compound of structure (Ilg); (Ilh), (Hi) or (Iij), X² is CH₂I. In other embodiments, X² is -CH₂OS0₂R⁹. In other embodiments, X² is C₁-C₅ alkyl optionally substituted with F. For example, in some embodiments, X² is C₁-C₅ alkyl substituted with F. In other embodiments, X² is unsubstituted C₁-C₅ alkyl. In other embodiments, X² 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 C₁-C₅ alkyl. In some embodiments of the compound of structure (II), the compound has one of the following structures (Ilk); (III), (Urn) or (lln):

(Urn) (lln)

In some embodiments of the compound of structure (Ilk); (III), (Urn) or (lln), R⁵ is OH. In other embodiments, R⁵ is I. In other embodiments, R⁵ is -OS0²R₉.

In any of the foregoing embodiments of the compound of structure (Ilk); (III), (Urn) or (lln), R⁶ is H. In some embodiments, R⁵ is OH and R⁶ is H.

In any of the foregoing embodiments of the compound of structure (Ilk); (III), (Urn) or (lln), Y² is OH. In other embodiments, Y² is H. In other embodiments, Y² is F. In other embodiments, Y² is I. In other embodiments, Y² is -OSO₂R₉.

In any of the foregoing embodiments of the compound of structure (Ilk); (III), (Urn) or (lln), Q² is H. In other embodiments, Q² is F.

In any of the foregoing embodiments of the compound of structure (Ilk); (III), (Urn) or (lln), X² is CH₂I. In other embodiments, X² is -CH₂OS0₂R⁹. In other embodiments, X² is C₁-C₅ alkyl optionally substituted with F. For example, in some embodiments X² is C₁-C₅ alkyl substituted with F. In other embodiments X² is unsubstituted C₁-C₅ alkyl. In other embodiments, X² 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 C₁-C₅ alkyl.

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

(IIo) (Hp)

In some embodiments of the compound of structure (IIo) or (Hp), R is OH. In other embodiments, R⁵ is I. In other embodiments, R⁵ is -OS0₂R⁹.

In any of the foregoing embodiments of the compound of structure (IIo) or (Hp), R⁶ is H. In some embodiments, R⁵ is OH and R⁶ is H.

In any of the foregoing embodiments of the compound of structure (IIo) or (Hp), X² is CH₂I. In other embodiments, X² is -CH₂OS0₂R⁹ In other embodiments, X² is Ci-C₅ alkyl optionally substituted with F. In other embodiments, X² is C₁-C5 alkyl substituted with F. In other embodiments, X² is unsubstituted C₁-C5 alkyl. In other embodiments, X² 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 C₁-C5 alkyl.

In any of the foregoing embodiments of the compound of structure (II), at least one of R⁷ or R⁸ is methyl. In other embodiments, each of R⁷ and R⁸ is methyl. In other embodiments, at least one of R⁷ or R⁸ is F. In other embodiments, each of R⁷ and R⁸ is F.

In any of the foregoing embodiments of the compound of structure (II), R⁹ is methyl or CF₃. In other embodiments, R⁹ is phenyl optionally substituted with methyl or nitro. In other embodiments, R⁹ is phenyl, p-methylphenyl or m-nitrophenyl.

In any of the foregoing embodiments of the compound of structure (II),

In some embodiments, Z² is O. In other embodiments, Z² is CH₂. In still other embodiments, each occurrence of Z is either O or CH₂, for example in some embodiments the compound comprise one or more ethylene glycol repeating units.

In some embodiments of any of the forgoing embodiments, n²is 0. In other embodiments, n² is 1. In other embodiments, n² is 2. In other embodiments, n² is 3. In other embodiments, n² is 4. In other embodiments, n² is 5. In other embodiments, n² is 6. In other embodiments, n² is 7. In other embodiments, n² is 8. In other embodiments, n² is 9. In other embodiments, n² is 10. In other embodiments, n² is 11. In other embodiments, n² is 12. In other embodiments, n² is 13. In other embodiments, n² is 14. In other embodiments, n² is 15.

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, R⁹ is methyl or CF₃. In other embodiments, R⁹ is phenyl optionally substituted with methyl or nitro. In other embodiments, R⁹ 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 ¹⁸F. In other embodiments, the reagent is [K⁺ 2,2,2-cryptand]¹⁸F or n-Bu₄N⁺¹⁸F.

Each R³ may independently be C₁-C5 alkyl. Each R³ may independently be C₁-C₄ alkyl. Each R³ may independently be C₁-C3 alkyl. Each R³ may independently be C₁-C₂ alkyl. Each R³ may independently be methyl. Each R³ may independently be C₂ alkyl. Each R³ may independently be C₃ alkyl. Each R³ may independently be C₄ alkyl. Each R³ may independently be C5 alkyl. Each R³ may independently be F.

Each R⁴ may independently be C₁-C5 alkyl. Each R⁴ may independently be C₁-C₄ alkyl. Each R⁴ may independently be Ci-C₃ alkyl. Each R⁴ may independently be Ci-C₂ alkyl. Each R⁴ may independently be methyl. Each R⁴ may independently be C₂ alkyl. Each R⁴ may independently be C₃ alkyl. Each R⁴ may independently be C₄ alkyl. Each R⁴ may independently be C5 alkyl. Each R⁴ may independently be F.

Each R⁷ may independently be C₁-C5 alkyl. Each R⁷ may independently be C₁-C₄ alkyl. Each R⁷ may independently be Ci-C₃ alkyl. Each R⁷ may independently be Ci-C₂ alkyl. Each R⁷ may independently be methyl. Each R⁷ may independently be C₂ alkyl. Each R⁷ may independently be C₃ alkyl. Each R⁷ may independently be C₄ alkyl. Each R⁷ may independently be C5 alkyl. Each R⁷ may independently be F.

Each R⁸ may independently be C₁-C5 alkyl. Each R⁸ may independently be C₁-C₄ alkyl. Each R⁸ may independently be Ci-C₃ alkyl. Each R⁸ may independently be Ci-C₂ alkyl. Each R⁸ may independently be methyl. Each R⁸ may independently be C₂ alkyl. Each R⁸ may independently be C₃ alkyl. Each R⁸ may independently be C₄ alkyl. Each R⁸ may independently be C5 alkyl. Each R⁸ 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 administred 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 (NH₂)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 ¹⁸F Compounds

33





41

43

44

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 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 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 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 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. 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 a 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-toluenesulfonic 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- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, procaine, N- ethylpiperidine, theobromine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, Ν,Ν-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 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, 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 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.

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.

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 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 judgement 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 PC3 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-dioxolan-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

[K⁺ 2,2,2-cryptand] ¹⁸F^"

or

Mes = — S-CH

I I nBu₄N^{+ 18}F^"

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 ¹⁸F moiety can then be incorporated into b via any number of methods, for example treatment with [K⁺ 2,2,2-cryptand]¹⁸F^" or n-Bu₄N⁺18F^" (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 ¹⁸F incorporation can be determined by one skilled in the art. General Reaction Scheme II

An exemplary compound of structure A can be prepared according to General reaction Scheme II. Reaction of D with an appropriately substituted 1,3- dioxolane, wherein L is an appropriate leaving group (e.g., chloro), yields compounds of structure E. Optically pure or racemic dioxolanes may be employed to yield the desired stereochemistry. Epoxidation of E with an appropriate reagent, for example an appropriately substituted glycidyl tosylate, results in compounds of structure F.

Various epoxidation reagents may be employed, including optically pure reagents which yield optically pure epoxides (e.g., + or - glycidyl tosylate). Treatment of F with an appropriate ring-opening reagent, for example CeCl₃x7H₂0, yields G. ¹⁸F may then be incorporated into G as described above in reference to General Reaction Scheme I.

In addition to ¹⁸F, various method for incorporation of fluorine (i.e., not ¹⁸F) 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, 3401-3411, 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 tetrabutylammonium 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. For example, epoxidation may precede dioxalone formation. 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 Formual I can be prepared by functionalizing a free hydroxyl 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)





60

61

65

66



70

71 EXAMPLES

All non-aqueous reactions were performed in flame-dried round bottomed flasks. The flasks were fitted with rubber septa and reactions were conducted under a positive pressure of argon unless otherwise specified. Stainless steel syringes were used to transfer air- and moisture-sensitive liquids. Flash column chromatography was performed as described by Still et al. (Still, W. C; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923) using 230-400 mesh silica gel. Thin-layer chromatography was 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 were visualized by exposure to ultraviolet light and a "Seebach" staining solution (700 mL water, 10.5 g Cerium (IV) sulphate tetrahydrate, 15.0 g molybdato phosphoric acid, 17.5 g sulphuric acid) followed by heating (~1 min) with a heating gun (-250 °C). Organic solutions were concentrated on Buchi R-l 14 rotatory evaporators at reduced pressure (15-30 torr, house vacuum) at 25-40 °C.

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

EXAMPLE 1

SYNTHESIS OF (S)-2-CHLORO-1-(4-(2-(4-((S)-2-¹⁸FLUORO-1- HYDROXYETHYL)PHENYL)PROPAN-2-YL)PHENYL)ETHANOL (1A)

Columbia Cancer Agency from H₂ ¹⁸0 via the ¹ 1⁵80, (p,n) ,¹1⁵8F_T nuclear reaction. After bombardment, the H₂ ¹⁸0 (~ 2 mL) containing 160 - 450 mCi ¹ 1^S8F_T was passed through a

QMA cartridge, and the ¹⁸F retained on the cartridge was eluted out with a solution of K₂CO₃ (7 mg) and kryptofix (K₂₂₂, 22 mg) in CH₃CN (0.3 mL) and water (0.3 mL) into a 4-mL reaction vial. The solution was evaporated at 120 °C, followed by two azeotropic distillations using 1 mL of CH₃CN. A solution of tetrahydropyran (THP) protected tosylate analogue (A) (2 mg) in DMSO (0.5 mL) was added, and the reaction vial was sealed and incubated at 100 °C for 20 min. Aqueous H₂S0₄ solution (0.5 N, 1 mL) was then added to remove the tetrahydropyranyl protecting groups. After another 5 min incubation at 100 °C, the reaction mixture was neutralized with 30% NaOAc aqueous solution (0.3 mL), and purified by HPLC under isocratic conditions (1 : 1 H₂0 /CH₃CN, 4.5 mL/min) on a Phenomenex Luna C-18 semi-preparative column (250 mm x 10 mm, 5 μιη) monitored on-line for UV absorption at 220 nm. The HPLC elution fraction containing la (t_R = 18.7 min, see Figure 1A) was collected, diluted with water, and passed through a light tC18 sep-pak cartridge. The trapped la on the cartridge was eluted out with DMSO (0.4 mL). For imaging studies, a fraction of the eluted DMSO solution was diluted with a 30% PEG solution to make a final la solution containing < 5% DMSO and with activity concentration at ~ 1.0 mCi/rnL.

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

EXAMPLE 2

BINDING OF COMPOUND 1A TO THE AF-1 IN THE AND OGE

RECEPTOR N-TERMINAL DOMAIN

Compound la was incubated on ice for 1 hour with recombinant protein AR. The results presented in Figure 2 indicate that compound la shows binding to the AF-1 in the AR NT. After 1 hour incubation on ice, compound la bound to the recombinant protein AR AF-1. Less binding of compound la was observed when AR AF-1 was pre-incubated with the corresponding ¹⁹F compound (compound Z). The same SDS-PAGE gel was stained with Coomassie blue for loading control.

EXAMPLE 3

ANDROGEN RECEPTOR N-TERMINAL DOMAIN BINDING STUDIES

Since specific binding to the AR NTD allows for detection of the AR NTD via methods described herein, compound Y, a non-radiolabeled hydroxyl analogue of compound 12, was tested for its ability to bind specifically to AR NTD. Data for both racemic Y and the R,S-diasteroemer of Y (the chlorohydrin substituent has the S configuration, and this diastereomer is noted as the "S" isomer in Figure 3). LNCaP cells treated with EPI-054 prior to cell lysis, Click chemistry, streptavidin beads and western blot analysis for biotin-labeled probes covalently bound to cellular proteins using antibodies to biotin or AR. The arrows in Figure 3 indicate a band corresponding to AR at 110 kDa. Note how few proteins bind to the biotinylated probe. Accordingly, the compounds of the present invention are expected to be useful for detection of AR NTD via PET imaging methods since a non-radiolabelled analogue thereof is a specific binder of the AR NTD.

EXAMPLE 4

IMAGING STUDIES

Mature male mice were injected with compound la (lOOuCi) either with or without prior blocking using 50mg/kg body weight compound Z. Data is presented in Figures 4 and 5. In mice, compound la is distributed throughout the animal evenly within the first 5 minutes including the brain. Activity in the blood clears within 30 - 40 minutes with the majority of the tracer found in the region of the gut. Compound la appears to be excreted via the liver rather than the kidney. Low activity was found in the bladder after 3 hours; bone and muscle uptake was also low. Referring to Figure 4, scanning over 3 hours shows that compound la targets androgen dependent tissue such as the seminal vesicles and prostate (NSVUP) while in the blocked animal (BSVUP) the levels remain constant. Neither the blocked (NTES) or unblocked testes (BTES) showed this same trend.

Consistent with compound Z targeting the AR, therapeutic doses of compound Z decrease the weight of androgen-dependent tissues in mature male mice and shows efficacy at lOmg/kg on CRPC xenografts. High therapeutic doses of compound Z (35 mg/kg oral daily) were not toxic even after 30 days. PET imaging agents are administered at a microdose compared to doses required for therapeutic response.

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.

Claims

1. A com ound having a structure of Formula I:

I or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

R¹ is F, ¹⁸F, OH or OG;

R² is H or F;

R³ and R⁴ are each independently F, F or C₁-C₅ alkyl;

Z is, at each occurrence, independently -0-, -S-, -SO₂-, -CH₂-, or

-C(Y)(Q>;

Q is H or F

X is CH₂F, CH₂ ¹⁸F; C₁-C₅ alkyl optionally substituted with F or ¹⁸F, CH₂OH or CH₂OG;

G is a moiety from Table I;

Y is H, F, ¹⁸F, OH or OG; and

n is an integer from 0 to 15;

wherein at least one of R¹, R³, R⁴, or Y is ¹⁸F or X is CH₂ ¹⁸F or a Ci- alkyl substituted with at least one ¹⁸F moiety.

3. The compound of claim 1 or 2, wherein the compound has one of the followin structures (Ic), (Id), (Ie) or (If):

(Ic) (Id)

(Ie) (if)

4. The compound of any of claims 1-3, wherein R¹ is OH.

5. The compound of any of claims 1-3, wherein R is H.

6. The compound of any of claims 1-5, wherein R¹ is OH and R² is H.

The compound of any of claims 1-6, wherein Z is -C(Y)(Q)-.

8. The compound of any of claims 1-7, wherein n is 1.

9. The compound of any of claims 1-8, wherein Y is F.

10. The compound of any of claims 1-8, wherein Y is F

11. The compound of any of claims 1-8, wherein Y is H.

12. The compound of any of claims 1-11, wherein Q is F.

13. The compound of any of claims 1-11, wherein Q is H.

14. The compound of any of claims 1-13, wherein X is CH₂ F

15. The compound of any of claims 1-8 or 12-14, wherein Y is OH.

16. The compound of claim 1, wherein the compound has one of the following structures (Ig); (Ih), (Ii) or (Ij):

(Ig) (Ih)

or

(Ii) (Ij)

17. The compound of claim 16, wherein R¹ is OH.

18. The compound of claim 16, wherein R² is H.

19. The compound of any of claims 16-18, wherein R¹ is OH and R² is H.

20. The compound of any of claims 16-19, wherein Y is OH.

21. The compound of any of claims 16-19, wherein Y is H. 22 The compound of any of claims 16-19, wherein Y is F.

23 The compound of any of claims 16-19, wherein Y is F.

24 The compound of any of claims 16-23, wherein Q is H.

25 The compound of any of claims 16-23, wherein Q is F.

26. The compound of any of claims 16-23, wherein X is C₁-C5 alkyl optionally substituted with a ¹⁸F moiety.

27. The compound of of claim 26, wherein X is C₁-C5 alkyl substituted with a ¹⁸F moiety.

The compound of of claim 26, wherein X is unsubstituted Ci alkyl.

29. The compound of any of claims 26-28, wherein X is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl.

30. The compound of claim 29, wherein the ¹⁸F moiety, when present, is at a terminal position of the C₁-C5 alkyl.

31. The compound of claim 1 , wherein the compound has one of the followin structures (Ik); (II), (Im) or (In):

(Ik) (II)

(Im) (In)

32. The compound of claim 31 , wherein R¹ is OH.

33. The compound of claim 31 , wherein R² is H.

34. The compound of any of claims 31-33, wherein R¹ is OH and R² is H.

35. The compound of any of claims 31-34, wherein Y is OH.

36. The compound of any of claims 31-34, wherein Y is H.

37. The compound of any of claims 31-34, wherein Y is F.

38. The compound of any of claims 31-34, wherein Y is ¹⁸F.

39. The compound of any of claims 31-38, wherein Q is H.

40. The compound of any of claims 31-38, wherein Q is F.

41. The compound of any of claims 31-40, wherein X is C₁-C₅ alkyl optionally substituted with a F moiety.

The compound of of claim 41, wherein X is C₁-C₅ alkyl substituted with a F moiety.

The compound of of claim 42, wherein X is unsubstituted Ci alkyl.

44. The compound of any of claims 41-43, wherein X is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl.

45. The compound of claim 44, wherein the ¹⁸F moiety, when present, is at a terminal position of the C₁-C5 alkyl.

46. The compound of claim 1, wherein the compound has one of the followin structures (Io) or (Ip):

(Io) (Ip)

47. The compound of claim 46, wherein R¹ is OH.

48. The compound of claim 46, wherein R² is H.

49. The compound of any of claims 46-48, wherein R¹ is OH and R² is H.

50. The compound of any of claims 46-49, wherein X is C₁-C₅ alkyl optionally substituted with a ¹⁸F moiety.

51. The compound of claim 50, wherein X is C₁-C₅ alkyl substituted with a ¹⁸F moiety.

52. The compound of claim 50, wherein X is unsubstituted C₁-C₅ alkyl.

53. The compound of any of claims 50-52, wherein X is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl.

54. The compound of claim 53, wherein the ¹⁸F moiety, when present, is at a terminal position of the C1-C5 alkyl.

55. The compound of any of claims 1-54, wherein at least one of R³ or R⁴ is methyl.

56. The compound of any of claims 1-54, wherein each of R³ and R⁴ is methyl.

57. The compound of any of claims 1-54, wherein at least one of R³ or R⁴ is F.

58. The compound of any of claims 1-54, wherein each of R³ and R⁴ is F.

The compound of claim 1 , wherein G

60. The compound of claim 1, wherein the compound has one of the following structures:

or a pharmaceutically acceptable salt or stereoisomer thereof.

61. A pharmaceutical composition comprising a compound of any one of claims 1 to 60, and a pharmaceutically acceptable carrier.

62. A method of imaging cancer, the method comprising administering the pharmaceutical composition of claim 61 to a subject and detecting the presence or absence of cancer by use of positron emission tomography.

63. The method of claim 62, wherein the method identifies the presence or absence of a tumor.

64. The method of claim 63, wherein the method identifies the location of a tumor.

65. The method of claim 62, wherein the cancer is prostate cancer.

66. The method of claim 65, wherein the prostate cancer is castration resistant prostate cancer.

67. The method of claim 65, wherein the prostate cancer is androgen-dependent prostate cancer.

68. The method of claim 62, wherein the method detects the presence of splice variants.

69. A compound having a structure of Formula II:

II or a salt or stereoisomer thereof, wherein:

R⁵ is F, OH, -OG², -OP, I or -OS0₂R⁹;

R⁶ is H or F;

R⁷ and R⁸ are each independently F, or C₁-C₅ alkyl;

R⁹ is CF₃, optionally substituted Ci-C₆ alkyl or optionally substituted aryl;

P is an alcohol protecting group;

Z² is, at each occurrence, independently -0-, -S-, -S0₂-, -CH₂-, or

-C(Y²)(Q²)-;

X² is CH₂F, CH₂I, C₁-C₅ alkyl optionally substituted with F, CH₂OH, CH₂OG², CH₂OP or -CH₂OS0₂R⁹;

G² is a moiety from Table I;

Q² is H or F

Y² is H, F, I, OH, -OG², -OP, or -OS0₂R⁹; and

n² is an integer from 0 to 15,

wherein at least one of R⁵ or Y is -OS0₂R⁹ or wherein X² is -CH₂OS0₂R⁹ or combinations thereof.

70. The compound of claim 69, wherein the compound has one of the following structures (II a) or (lib):

72. The compound of any of claims 69-71, wherein R⁵ is OH.

73. The compound of any of claims 69-71, wherein R⁵ is I.

74. The compound of any of claims 69-71, wherein R⁵ is -OS0₂R⁹.

75. The compound of any of claims 69-71, wherein R⁶ is H.

76. The compound of any of claims 69-71, wherein R⁵ is OH and R⁶ is H.

77. The compound of any of claims 69-76, wherein Z² is

-C(Y²)(Q²)-.

The compound of any of claims 69-76, wherein

79. The compound of any of claims 69-78, wherein Y² is F.

80. The compound of any of claims 69-78, wherein Y² is I.

The compound of any of claims 69-78, wherein Y² is -OS0₂

82. The compound of any of claims 69-78, wherein Y² is H.

83. The compound of any of claims 69-78, wherein Y² is OH.

84. The compound of any of claims 69-83, wherein Q² is F.

85. The compound of any of claims 69-83, wherein Q² is H.

86. The compound of any of claims 69-85, wherein X² is CH₂F.

87. The compound of any of claims 69-85, wherein X² is CH₂I.

88. The compound of any of claims 69-85, wherein X² is

-CH₂OS0₂R⁹.

89. The compound of claim 69, wherein the compound has one of the following structures (Ilg); (Ilh), (Hi) or (Ilj):

(iig) (Ilh)

(Hi) (Ilj)

90. The compound of claim 89, wherein R⁵ is OH.

91. The compound of claim 89, wherein R⁵ is I.

The compound of claim 89, wherein R⁵ is -OS0₂

93. The compound of claim 89, wherein R⁶ is H.

94. The compound of any of claims 89, wherein R⁵ is OH and R⁶ is

H.

95. The compound of any of claims 89-94, wherein Y is OH.

96. The compound of any of claims 89-94, wherein Y is H.

97. The compound of any of claims 89-94, wherein Y is F.

98. The compound of any of claims 89-94, wherein Y² is I.

The compound of any of claims 89-94, wherein Y² is -OS0₂

100. The compound of any of claims 89-99, wherein Q² is H.

101. The compound of any of claims 89-99, wherein Q² is F.

102. The compound of any of claims 89-101, wherein X² is CH₂I.

103. The compound of any of claims 89-101, wherein X² is

-CH₂OS0₂R⁹.

104. The compound of any of claims 89-101, wherein X² is Ci-C₅ alkyl optionally substituted with F.

105. The compound of any of claim 104, wherein X² is C₁-C5 alkyl substituted with F.

The compound of of claim 104, wherein X² is unsubstituted

Ci-C₅ alkyl.

The compound of any of claims 104-106, wherein X² is methyl ethyl, n-propyl, isopropyl, n-butyl or propargyl.

108. The compound of claim 107, wherein the F moiety, when present, is at a terminal position of the C₁-C5 alkyl.

107. The compound of claim 69, wherein the compound has one of the following structures (Ilk); (III), (Urn) or (Iln):

(Urn) (Iln)

108. The compound of claim 107, wherein R is OH.

109. The compound of claim 107, wherein R is I.

The compound of claim 107, wherein R⁵ is -OS0₂

111. The compound of claim 107, wherein R is H.

112. The compound of any of claims 107, wherein R⁵ is OH and R⁶ is

H.

113. The compound of any of claims 107-111, wherein Y is OH.

114. The compound of any of claims 107-111, wherein Y is H.

115. The compound of any of claims 107-111, wherein Y is F.

116. The compound of any of claims 107-111, wherein Y² is I.

117. The compound of any of claims 107-111, wherein Y² is

118. The compound of any of claims 107-117, wherein Q² is H.

119. The compound of any of claims 107-117, wherein Q² is F.

120. The compound of any of claims 107-119, wherein X² is CH₂I.

121. The compound of any of claims 107-119, wherein X² is

-CH₂OS0₂R⁹.

122. The compound of any of claims 107-119, wherein X² is C₁-C5 alkyl optionally substituted with F.

123. The compound of any of claim 122, wherein X² is C₁-C5 alkyl substituted with F.

124. The compound of of claim 122, wherein X² is unsubstituted

Ci-C₅ alkyl.

125. The compound of any of claims 122-124, wherein X² is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl.

126. The compound of claim 125, wherein the F moiety, when present, is at a terminal position of the C₁-C5 alkyl.

127. The compound of claim 69, wherein the compound has one of the following structures (IIo) or (Hp):

(IIo) (Hp)

128. The compound of claim 127, wherein R⁵ is OH.

129. The compound of claim 127, wherein R⁵ is I.

The compound of claim 127, wherein R⁵ is -OS0₂

131. The compound of claim 127, wherein R⁶ is H.

132. The compound of any of claims 127-131, wherein R⁵ is OH and

R⁶ is H.

133. The compound of any of claims 127-132, wherein X² is CH₂I.

133. The compound of any of claims 127-132, wherein X² is

-CH₂OS0₂R⁹.

134. The compound of any of claims 127-132, wherein X² is C₁-C₅ alkyl optionally substituted with F.

135. The compound of any of claim 134, wherein X² is C₁-C₅ alkyl substituted with F.

The compound of of claim 134, wherein X² is unsubstituted

Ci-C₅ alkyl.

137. The compound of any of claims 134-136, wherein X² is methyl, ethyl, n-propyl, isopropyl, n-butyl or propargyl.

138. The compound of claim 137, wherein the F moiety, when present, is at a terminal position of the C1-C5 alkyl.

139. The compound of any of claims 69-138, wherein at least one of R⁷ or R⁸ is methyl.

140. The compound of any of claims 69-138, wherein each of R⁷ and

R⁸ is methyl.

141. The compound of any of claims 69-138, wherein at least one of

R⁷ or R⁸ is F.

142. The compound of any of claims 69-138, wherein each of R⁷ and

R⁸ is F.

143. The compound of any of claims 69-138, wherein R⁹ is methyl or

CF₃.

144. The compound of any of claims 69-138, wherein R⁹ is phenyl optionally substituted with methyl or nitro.

145. The compound of any of claims 69-138, wherein R⁹ is phenyl, p-methylphenyl or m-nitrophenyl.

The compound of claim 69, wherein G

147. The compound of claim 69, wherein the compound has one of the following structures:

or a pharmaceutically acceptable salt or stereoisomer thereof.

148. The compound of claim 147, wherein R⁹ is methyl or CF 3 ·

The compound of claim 147, wherein R⁹ is phenyl optionally substituted with methyl or nitro.

The compound of claim 147, wherein R⁹ is phenyl

p-methylphenyl or m-nitrophenyl.

A method for preparing a compound of structure (I), the method comprising reacting a compound of structure (II) with a reagent comprising ¹⁸F.

152. The method of claim 151, wherein the reagent is [K 2,2,2- cryptand]¹⁸F^" or n-Bu₄N⁺¹⁸F^~.