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ENDOCRINE AND DIABETES

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

Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio (J.Y., C.E.B., J.T.D.); and Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee, Memphis, Tennessee (V.A.N., S.M.M., S.S.H., D.D.M.)

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 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.

Address correspondence to: Dr. James T. Dalton, 500 West 12th Avenue, L.M. Parks Hall, Room 242, Columbus, OH 43210. E-mail: dalton.1{at}osu.edu