Preclinical Evaluation and First-in-Human PET Study of Al¹⁸F-Labeled Biphenyl-Based Dimeric PSMA Tracers

Prostate-specific membrane antigen (PSMA) is a crucial target for prostate cancer (PCa) imaging and therapy. This study developed a novel [¹⁸F]AlF-labeled dimeric PSMA tracer, [¹⁸F]AlF-PSMA-N5, using a biphenyl scaffold to improve imaging efficacy. Seven biphenyl-based ligands were synthesized and evaluated for PSMA binding affinity and in vivo performance in 22Rv1 tumor-bearing mice. [¹⁸F]AlF-PSMA-N5 exhibited high PSMA affinity (K_i = 0.31 ± 0.06 nM), acceptable radiochemical yield (25.6% ± 6.6%), and high purity (>95%). In xenograft models, it demonstrated high tumor uptake (SUV_max = 3.15) and a tumor-to-muscle ratio (T/M) of 22.57. Preliminary first-in-human studies in PCa patients showed that [¹⁸F]AlF-PSMA-N5 successfully identified primary tumors and metastatic lesions, offering superior image contrast and higher T/M ratios compared to [⁶⁸Ga]Ga-PSMA-11. Additionally, it provided comparable tumor uptake and T/M ratios to [¹⁸F]DCFPyL. These findings highlight [¹⁸F]AlF-PSMA-N5 as a promising PET radiotracer for PCa imaging, with improved imaging quality and reduced nonspecific uptake.