title: 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 approximately 25% 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) = 4.4 nM) in a whole-cell binding assay using COS-7 cells transfected with human AR than testosterone (K(i) = 32.9 nM) and dihydrotestosterone (K(i) = 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.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Casey E
authors.initials: CE
authors.lastname: Bohl
authors.forename: Vipin A
authors.initials: VA
authors.lastname: Nair
authors.forename: Suni M
authors.initials: SM
authors.lastname: Mustafa
authors.forename: Seoung Soo
authors.initials: SS
authors.lastname: Hong
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D008024:Ligands; D009570:Nitriles; D019275:Radiopharmaceuticals; D011944:Receptors, Androgen; C510437:S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide