Synthesis and preclinical evaluation of 68Ga-labeled PSMA tracers with improved pharmacological properties

Prostate cancer (PCa) is one of the most common tumors in men, with the overexpression of prostate-specific membrane. In this study, we developed four new 68Ga-labeled PSMA-targeting tracers by introducing quinoline, phenylalanine and decanoic acid groups to enhance their lipophilicity, strategically limiting their metabolic pathway through the urinary system. Four radiotracers were synthesized with radiochemical purity > 95%, and exhibited high stability in vivo and in vitro. The inhibition constants (Ki) of SDTWS01-04 to PSMA were in the nanomolar range (< 10 nM). Micro PET/CT imaging and biodistribution analysis revealed that 68Ga-SDTWS01 enabled clear tumor visualization in PET images at 1.5 h post-injection, with excellent pharmacokinetic properties. Notably, the kidney uptake of 68Ga-SDTWS01 significantly reduced, with higher tumor-to-kidney ratio (0.36 ± 0.02), tumor-to-muscle ratio (24.31 ± 2.10), compared with 68Ga-PSMA-11 (T/K: 0.15 ± 0.01; T/M: 14.97 ± 1.40), suggesting that 68Ga-SDTWS01 might be applied in the detection of local metastatic lesion, with minimized radiation toxicity to the urinary system. Moreover, SDTWS01 with a chelator DOTA could also label 177Lu and 225Ac, which could be used for the treatment for PCa.