A Novel PSMA-Targeted Theragnostic Agent: Preclinical Validation of Dual-Modality Imaging and Targeted Radionuclide Therapy

Background : Targeted radionuclide therapy (TRT) has remarkable potential in the diagnosis and treatment of tumors. Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is markedly overexpressed in prostate cancer cells, which renders it a premier target for theragnostic applications. This study sought to develop a new anti-PSMA small molecule TM-1labeled with ⁶⁸ Ga or ¹⁷⁷ Lu and assess the biodistribution via Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography Imaging (SPECT). Furthermore, the antitumor efficacy of TM-1 in tumor-bearing mice was extensively evaluated. Result : The radiotracer exhibited high radiochemical purity (RCP>95%) and stability in PBS. In vitro , a significant reduction in the uptake rate was observed between the experimental wells and block wells (0.31±0.01 vs 0.08±0.01, p<0.05), confirming PSMA-specific binding. Biodistribution data showed specific uptake in PSMA-positive tumor (9.41±3.11% ID/g for ¹⁷⁷ Lu-TM-1 after 1h). Both PET and SPECT imaging showed rapid and sustained accumulation of the radiotracer at tumor sites (4.92±2.00% ID/g for PET and 6.56%±1.09% ID/g for SPECT after 1h), and the tumor tissues were clearly characterized. In therapeutic efficacy studies, the tumor volume of mice in the high-dose group significantly decreased compared to control (430.00±145.99 vs 1115.75±134.16 mm ³ , p<0.01). Conclusion ：A new PSMA tracer, TM-1, was successfully synthesized and radiolabeled in our study. Both in vitro and in vivo experiments demonstrated its ability to specifically target and treat PSMA-positive tumors.