多肽受体介导的核素治疗（PRRT）是极具潜力的核医学肿瘤治疗技术，但放射性肾损伤严重制约PRRT的疗效。放射性酶切清除策略可通过在放射性核素和探针间加入中性内肽酶（NEP）等特异性酶切序列的方式，实现二者在肾脏的特异性切割分离，避免核素的重吸收，降低核素在肾脏的浓聚。然而，我们与国内外学者研究表明，由于底物与NEP酶的空间位点结构及功能特点不匹配，传统酶切序列MVK的活体应用效果不理想。本研究拟针对NEP的结构特点，设计并筛选更优的酶切序列ABK，构建具有优选酶切序列的ABK-PSMA-617新探针，以期通过64Cu-PET显像揭示酶切清除策略在PRRT中应用的可行性，并对活体肿瘤及主要脏器的辐射剂量进行定量；通过177Lu治疗研究，明确新探针在疗效及肾损伤预防中的实际价值。本课题有望通过提供放射性酶切清除新序列，为解决PRRT肾损伤提供新思路，为提高PRRT的临床疗效提供新方案。

Peptide receptor-mediated radionuclide therapy (PRRT) is a highly promising nuclear medicine tumor treatment technology, but radioactive kidney injury severely restricts the tumor efficacy of PRRT. The radioactive enzyme-clearing strategy can be achieved by adding a specific sequence, which can be restricted by enzymes such as neutral endopeptidase (NEP), between the radionuclide and the probe. The modified probe can thus be specifically cleaved and separated in kidneys by the function of NEP, thereby avoiding the reabsorption of the radionuclides and reducing the concentration of radioactivity in the kidney. However, researches of domestic and foreign scholars show that the traditional application of MVK is not ideal, and the feasibility and effectiveness of this strategy in PRRT has not been studied. In this study, we designed and screened an optimal restriction enzyme sequence ABK for the structure of NEP, and constructed a new probe ABK-PSMA-617 with the preferred restriction enzyme sequence, in order to testify the feasibility of enzymatic excision clearance principle in PRRT and quantify the radiation dose of the living body by 64Cu-PET imaging. Furthermore, we plan to clarify the practical value of the new probe in the PRRT therapeutic efficacy and prevention of renal injury, through the 177Lu treatment study. This topic is expected to provide new sequences for radioactive enzyme digestion, provide new ideas for solving lung injury in PRRT, and provide new solutions for improving the clinical efficacy of PRRT.