Preclinical Pharmacology of a Nonsteroidal Ligand for Androgen Receptor-Mediated Imaging of Prostate Cancer

Abstract

Proper management of prostate cancer patients is highly dependent on the spread of the disease. High expression levels of the androgen receptor (AR) in prostate tumor offer a target for identifying cancer metastasis. We investigated the use of nonsteroidal AR ligands for receptor-mediated imaging as a diagnostic tool for prostate cancer staging. Compound S-26 [S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide]was identified from a series of iodinated ether-linked derivatives of bicalutamide due to its high-AR binding affinity of 3.3 nM (which is similar to testosterone and ϳ25% of the binding affinity of dihydrotestosterone) in an in vitro competitive binding assay using rat prostate cytosol. Furthermore, S-26 exhibited a greater binding affinity (K i ϭ 4.4 nM) in a whole-cell binding assay using COS-7 cells transfected with human AR than testosterone (K i ϭ 32.9 nM) and dihydrotestosterone (K i ϭ 45.4 nM). We also confirmed that sex hormone-binding globulin (SHBG), a plasma protein that binds steroids with high affinity, does not bind with S-26. Cotransfection studies with the estrogen, progesterone, and glucocorticoid receptor indicated that S-26 does not cross-react with other members of the steroid hormone receptor family. The nonsteroidal structure, high-AR binding affinity, specificity, and lack of binding to SHBG indicate that S-26 exhibits favorable properties for further development as an imaging agent for prostate cancer.

Pharmacokinetics, biodistribution and metabolism of a novel selective androgen receptor modulator designed for prostate cancer imaging

“…For example, rats do not express SHBG, which has a high binding affinity to steroids, while humans do (29,30). Previous studies (18) show that non-steroidal ligands like S-26 do not bind to SHBG and other steroid receptors. Therefore, we expected that the rat would be a reasonable animal model for biodistribution studies of non-steroidal ligands.…”

“…3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodo-phenyl)-propionamide (S-26), its trimethyltin precursor, and an internal standard ( Fig. 1) were synthesized and characterized in our laboratories as previously described (7,18,20,21 Pharmacokinetic studies. Male Sprague-Dawley rats weighing 195-238 g were used for pharmacokinetic studies.…”

“…We completed extensive studies on the molecular and preclinical pharmacology of these compounds, advancing them from high affinity but metabolically labile ligands (13) to tissue-selective drugs with promising in vivo pharmacologic activity (9,10,12,(14)(15)(16)(17). These studies on the structureactivity relationships for AR binding and activation provide important information for rationally modifying the structures of non-steroidal ligand to obtain novel compounds for AR mediated imaging of prostate cancer (18). Our previous studies showed that non-steroidal AR ligands incorporating iodine in either the A ring or B ring of the aryl propionamide pharmacophore retain high binding affinity to the AR (18)(19)(20)(21).…”

“…These studies on the structureactivity relationships for AR binding and activation provide important information for rationally modifying the structures of non-steroidal ligand to obtain novel compounds for AR mediated imaging of prostate cancer (18). Our previous studies showed that non-steroidal AR ligands incorporating iodine in either the A ring or B ring of the aryl propionamide pharmacophore retain high binding affinity to the AR (18)(19)(20)(21). In our previous report, S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodo-phenyl)-propionamide (referred to as S-26 hereafter as in ref.…”

“…In our previous report, S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodo-phenyl)-propionamide (referred to as S-26 hereafter as in ref. 18) was shown to exhibit favorable properties for further development as an imaging agent for prostate cancer, i.e., high-AR binding affinity of 3.3 nM (which is similar to testosterone), high specificity (does not cross-react with other members of the steroid hormone receptor family) and lack of binding to SHBG, a plasma protein that binds steroids with high affinity (18). S-26 ( Fig.…”