Synthesis, Preclinical Evaluation, and First-in-Human PET Study of [⁶⁸Ga]-Labeled Biphenyl-Containing PSMA Tracers

Radioisotope-labeled prostate-specific membrane antigen (PSMA) PET tracers have gained popularity in diagnosing prostate cancer (PCa). This study aimed to improve the affinity and tumor-targeting capabilities of new PSMA tracers by increasing the number of pharmacophores that specifically bind to PSMA. Using biphenyl as a core scaffold, we investigated the relationship among spacer segments, affinity, and pharmacokinetic properties. In preclinical PET studies on mice with 22Rv1 tumors, compared with [⁶⁸Ga]Ga-PSMA-11 (SUV_max = 3.37), [⁶⁸Ga]Ga-PSMA-D5 (K_i = 0.15) showed higher tumor uptake (SUV_max = 3.51) and lower renal uptake (T/K = 1.84). In the first-in-human study, [⁶⁸Ga]Ga-PSMA-D5 effectively detected small PCa-associated lesions and distant metastases. The advantages of [⁶⁸Ga]Ga-PSMA-D5 include high tumor uptake, straightforward synthesis, and labeling, making it a promising PSMA PET tracer. Furthermore, [⁶⁸Ga]Ga-PSMA-D5 contains a DOTA chelator, allowing convenient labeling with therapeutic radionuclides such as ¹⁷⁷Lu and ²²⁵Ac, providing the potential for targeted radioligand therapy in PCa.