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.