Abstract Molecular imaging in oncology aims to complement the growing repertoire of chemotherapies with noninvasive diagnostic tools to measure pharmacodynamics and improve predictions of disease response. In prostate cancer, several chemotherapeutic strategies have been developed to inhibit androgen receptor (AR) function, and currently show promise in treating advanced, castration resistant disease. Among these, competitive inhibitors of steroid agonist/receptor interactions have been effectively staged with fluorine-18-fluoro-5α-dihydrotestosterone, an AR agonist compatible with quantitative PET imaging. However, some allosteric inhibitors of AR do not impact agonist/receptor interaction (or AR stability) and currently cannot be evaluated with a quantitative imaging technology. We address this problem here by presenting evidence that prostate specific membrane antigen is a diagnostic marker of allosteric AR inhibition. In culture or in xenograft models of LNCaP, 22Rv1, LAPC4, and VCaP, PSMA is repressed by androgen treatment. Ablation of AR with siRNA inhibits the hormone-mediated suppression of PSMA, directly implicating AR in the mechanism. We further show that PSMA suppression is antagonized by several competitive and allosteric AR inhibitors. Finally, we conducted a pilot study with 22Rv1 xenografts to demonstrate that 64Cu-DOTA-J591, a monoclonal antibody designed for clinical PET imaging of PSMA, quantitatively detects hormone-mediated PSMA suppression. Collectively, these results promote the use of PSMA imaging reagents in the clinic to stage allosteric AR inhibitors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B207.