Biphenyl-Trimeric PSMA Theranostic Platform Enables PET Imaging and Optical Detection of Prostate Cancer

Prostate cancer (PCa) diagnosis faces challenges with current imaging tracers in sensitivity and contrast. We developed a biphenyl-trimeric PSMA-targeted theranostic system to address these challenges. A suite of trimeric PSMA probes (PSMA-T0–T6) was synthesized using a biphenyl scaffold and variable linkers, showing exceptional PSMA affinity (Ki = 0.11–0.60 nM). Preclinical studies demonstrated that [68Ga]Ga-PSMA-T3 provided superior tumor uptake (SUVmax 1.16 vs 0.61) and tumor-to-background ratios (TBR 26.82 vs 19.89) over [68Ga]Ga-PSMA-11 in 22Rv1 tumor-bearing mice. The optical counterpart, ICG-conjugated PSMA-T6, prolonged tumor retention with high tumor-to-muscle ratio (T/M = 7.3 at 24 h) and remarkable ex vivo specificity (T/M = 41.9). In first-in-human PET studies, [68Ga]Ga-PSMA-T3 showed comparable and enhanced detection rates of primary and metastatic lesions, particularly in liver and bone metastases, with higher TBR values than [68Ga]Ga-PSMA-11. Our biphenyl-trimeric PSMA platform demonstrates translational potential for enhanced diagnostic sensitivity and intraoperative management of PCa.