Knowledge of the presence and extent of disease plays a major role in clinical management of prostate cancer, as it provides meaningful information as to which therapy to choose and who might benefit from this therapy. The wide expression of androgen receptor (AR) in primary and metastatic prostate tumors offers a cellular target for receptor-mediated imaging of prostate cancer. In our previous study, a non-steroidal AR ligand, S-26 [S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide] showed promising in vitro pharmacological properties as an AR-mediated imaging agent, with high AR binding affinity and AR specificity. The overall goal of this study was to characterize the in vivo metabolic and biodistribution profile of S-26 in rats. Non-compartmental pharmacokinetic analysis of S-26 in rat plasma showed that clearance (CL), volume of distribution (Vdss), and half-life (T1/2) of S-26 were 0.30±0.07 l/h/kg, 1.44±0.33 l/kg, and 4 h, respectively, after intravenous (i.v.) administration. Dose proportionality (1, 10 and 30 mg/kg) studies suggested that the pharmacokinetics of S-26 are dose-independent. The plasma concentrations of all 3 doses were further simultaneously fitted with a two-compartmental model and the results were similar to those obtained from non-compartmental analysis. Biodistribution studies using 125I-labeled S-26 indicated that it did not specifically target AR-rich tissue (e.g. prostate). A substantial amount of radioactivity recovered from thyroid gland indicated the release of free iodine. In metabolism studies, unchanged S-26 and its metabolites were detected in rat urine and fecal samples. Oxidation, de-iodination, hydrolysis, and sulfate conjugation were the major metabolic pathways of S-26 in rats, with de-iodination representing a unique metabolic pathway of S-26 among other selective androgen receptor modulators. In conclusion, the extensive plasma clearance and de-iodination of S-26 likely contribute to its lack of AR tissue selectivity in vivo. Future studies using metabolically stable ligands with less lipophilicity and higher AR binding affinity may represent a promising and rational approach for AR-mediated imaging.

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