Direct Androgen Receptor Antagonism Enhances Therapeutic PSMA Radioligand Uptake in Prostate Cancer Models

Background Prostate-specific membrane antigen (PSMA) is a central target for prostate cancer theranostics. Androgen receptor (AR) signaling has been implicated in regulating PSMA expression; however, whether different modes of AR pathway inhibition uniformly translate into enhanced functional radioligand uptake, particularly for therapeutic applications, remains incompletely defined. Methods AR-positive (LNCaP, C4-2) and AR-negative (PC3 PSMA +) prostate cancer models were investigated; parental PC3 cells served as PSMA-negative controls. Cells were treated with the direct AR antagonists enzalutamide and apalutamide or with the androgen biosynthesis inhibitor abiraterone. PSMA surface expression was quantified by flow cytometry. Functional uptake of [ 18 F]PSMA-1007 and [ 177 Lu]Lu-PSMA I&T was assessed by gamma counting. Glucose metabolism was evaluated using [ 18 F]FDG uptake, and PSA secretion was measured as a pharmacodynamic readout of AR pathway inhibition. Results Direct AR antagonism significantly increased PSMA surface expression in AR-positive models and translated into enhanced uptake of the therapeutic radioligand [ 177 Lu]Lu-PSMA I&T, with particularly pronounced effects in the castration-resistant C4-2 model. Diagnostic tracer uptake was also increased, though less consistently across models. In contrast, abiraterone did not induce consistent functional enhancement of radioligand accumulation despite PSMA upregulation in selected settings. AR-negative PC3 PSMA + cells exhibited stable baseline PSMA expression but showed no significant changes in PSMA levels or radioligand uptake following AR antagonist treatment. [ 18 F]FDG uptake was reduced under AR inhibition in AR-positive models, indicating that enhanced PSMA-targeted uptake was not driven by global metabolic activation. Conclusion Direct AR antagonism enhances functional PSMA availability and increases short-term uptake of PSMA-targeted radioligands in AR-positive prostate cancer models. These findings provide mechanistic support for AR-mediated modulation of PSMA-targeted radioligand delivery and warrant further translational investigation.