基于代谢位点氘代化策略探索研制“PLP-酶逃逸”氟-18氨基酸探针

氟-18氨基酸在PET肿瘤显像应用中极具发展潜力，但作为机体外来物质，其在体内代谢酶作用下常面临潜在的脱氟问题，给这类探针的研制带来了许多困难和挑战。PLP-酶是天然或合成氨基酸主要代谢酶，其催化反应实质是一种碳-氢键断裂并发生氢原子转移过程。基于前期工作，我们推测：将氟-18氨基酸分子中涉及代谢位点的氢替换为氘，可减缓其在PLP-酶作用下的分解速率并提高体内稳定性，从而解决脱氟难题。在此，本项目拟以[18F]三氟甲基蛋氨酸为先导化合物，设计构建氟-18氘代氨基酸探针；随后经详细的体内外生物评价研究，明确其摄取转运机制及在PLP-酶作用下的稳定性，分析用于PET胶质瘤显像潜力；最终筛选出体内稳定探针，并实现上述推测的合理性验证。项目完成后有望建立氘代氨基酸PET显像新模式，为后续该“氘代化策略”适用性研究提供重要实验基础，并为将来新型氟-18氨基酸探针的研制提供规避脱氟风险新思路。

Fluoro-18 amino acids have great potential in PET tumor imaging, but as foreign substances in the body, they often face a potential problem of defluorination under catalysis of metabolic enzymes in vivo, thus giving many difficulties and challenges in the development of this kind of probes. PLP-enzyme is the main metabolic enzyme of natural or synthetic amino acids, and its catalytic reaction is, in essence, a carbon-hydrogen bond breaking and hydrogen-transfer process. On the basis of our previous studies, we speculated that the replacement of hydrogen with deuterium in the metabolic sites of amino acids can slow down their decomposition rate under catalysis of PLP-dependent enzymes and improve the stability of the probes in vivo, thereby solving the above problems. Herein, this project intends to use [18F]trifluoromethyl methionine as a lead compound for the design and development of fluoro-18 deuterium amino acid probes. Subsequently, the in vivo and in vitro biological evaluation studies will be conducted to clarify the transport mechanism of the tracers and their stability under catalysis of the PLP-enzyme, and to explore the capability of the tracers for PET imaging of glioma. Finally, the in vivo stabilization probe will be screened out and the rationality of the above speculation will be verified. After the completion of this project, it is expected to establish a new pattern for PET imaging with deuterium amino acids, which will provide an important experimental basis for the follow-up studies on the applicability of this "deuteration strategy", and bring a new method for the development of novel 18F-labelled amino acid probes to avoid the risk of defluorination.