Prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals have become some of the most promising tools for the diagnosis and therapy prostate cancer (PCa). The structure of existing PSMA-targeted PET tracers still needs to be optimized to improve their pharmacokinetic properties and tumor-to-background ratio. In this study, we modified the structure of a well-studied PSMA tracer, and six novel tracers with variable hydrophilicity and pharmacokinetics were developed and evaluated both in vitro and in vivo. All of the novel tracers showed high hydrophilicity (log p = −2.99 ± 0.33 to −3.49 ± 0.01), rapid clearance rates (elimination half-times = 15.55 to 35.97 min), and high affinity for PSMA (Ki = 8.11 ± 0.49 to 42.40 ± 2.11 nM) in vitro. Specific cell binding and micro-PET experiments showed that [⁶⁸Ga]Ga-PSMA-Q displayed the highest specific PSMA+ cell uptake (3.75 ± 0.35 IA%/10⁶ at 60 min), tumor uptake (SUVmax = 0.97 ± 0.24 at 60 min p.i.), and tumor-to-muscle ratio (59.33 ± 5.72 at 60 min p.i.), while the tumor-to-muscle ratio was much higher than that of [⁶⁸Ga]Ga-PSMA-617. The results of this study validate the clinical potential of [⁶⁸Ga]Ga-PSMA-Q for PET imaging and further targeted therapy of prostate cancer.

Clinical trials have shown the significant efficacy of [¹⁷⁷Lu]Lu-PSMA-617 for treating prostate cancer. However, the pharmacokinetic characteristics and therapeutic performance of [¹⁷⁷Lu]Lu-PSMA-617 still need further improvement to meet clinical expectations. The aim of this study was to evaluate the feasibility and therapeutic potential of three novel ¹⁷⁷Lu-labeled ligands for the treatment of prostate cancer. The novel ligands were efficiently synthesized and radiolabeled with non-carrier added ¹⁷⁷Lu; the radiochemical purity of the final products was determined by Radio-HPLC. The specific cell-binding affinity to PSMA was evaluated in vitro using prostate cancer cell lines 22Rv1and PC-3. Blood pharmacokinetic analysis, biodistribution experiments, small animal SPCET imaging and treatment experiments were performed on normal and tumor-bearing mice. Among all the novel ligands developed in this study, [¹⁷⁷Lu]Lu-PSMA-Q showed the highest uptake in 22Rv1 cells, while there was almost no uptake in PC-3 cells. As the SPECT imaging tracer, [¹⁷⁷Lu]Lu-PSMA-Q is highly specific in delineating PSMA-positive tumors, with a shorter clearance half-life and higher tumor-to-background ratio than [¹⁷⁷Lu]Lu-PSMA-617. Biodistribution studies verified the SPECT imaging results. Furthermore, [¹⁷⁷Lu]Lu-PSMA-Q serves well as an effective therapeutic ligand to suppress tumor growth and improve the survival rate of tumor-bearing mice. All the results strongly demonstrate that [¹⁷⁷Lu]Lu-PSMA-Q is a PSMA-specific ligand with significant anti-tumor effect in preclinical models, and further clinical evaluation is worth conducting.