新型18F标记谷氨酰胺肿瘤显像剂的研究

PET imaging technology for tumor diagnosis with high sensitivity, high specificity, good security and so on, the development is very rapid. PET tumor diagnosis is the key to find a specific high imaging agent, and glutamine metabolism characteristics of the development of glutamine imaging agent is still in vivo defluorination, low tumor value, specificity and other issues, leading to clinical application Limited. Based on the existing research and ensuring that the target compound is still biologically active, the project aims to modify the structure of glutamine by changing the 18F marker site and the type of transporter carrier. The design and synthesis of hexamethylene and tetracarbon glutamine Derivatives, dipeptide derivatives, benzyl glutamine derivatives and corresponding labeled precursors. The performance of the marker was evaluated by bioassay. The structure and bioactivity of the imaging agent, the labeling site, the type of transport carrier, Tumor uptake relationship between the final screening of the highest stability in vivo, the strongest specificity of the new 18F labeled glutamine tumor diagnostic imaging agent. This project has developed a new type of 18F labeled tumor diagnostic medicine with independent intellectual property rights in China, which will fill the gaps in this field, which is of great significance to the development of new drugs in China, the promotion of PET and the economic development.

PET显像技术用于肿瘤诊断具有灵敏度高、特异性高、安全性好等特点，发展非常迅速。PET肿瘤诊断的关键是寻找特异性高的显像剂，而以谷氨酰胺代谢特征研发的谷氨酰胺类显像剂仍存在体内脱氟、肿瘤摄取值低、特异性差等问题，导致临床应用受限。本项目在现有研究基础上，保证目标化合物仍具有生物活性的前提下，拟通过改变18F标记位点和转运载体类型等手段修饰谷氨酰胺结构，设计并合成六碳和四碳谷氨酰胺衍生物、二肽衍生物、苄基谷氨酰胺衍生物以及相应的标记前体，并通过生物实验评价标记物成像的性能，明确显像剂结构与生物活性、标记位点、转运载体类型、肿瘤摄取之间的关系，最终筛选出体内稳定性最高、特异性最强的新型18F标记谷氨酰胺肿瘤诊断显像剂。本项目研发出的具有我国自主知识产权的新型18F标记肿瘤诊断药物，将填补我国在该领域的空白，对我国新药研发、PET的推广和经济发展具有重要意义。

谷氨酰胺是肿瘤的第二大能量来源，基于谷氨酰胺骨架修饰而开发谷氨酰胺代谢型PET显像剂有望应用于肿瘤的诊疗。首先在谷氨酰胺的4位碳上引入苄氧烷基得到(2S, 4S)4-[18F]FEBGln，其依靠L型和ASC型转运。这进一步验证了引入苯环，氨基酸的转运机制偏向L型转运。生物评价表明，其可以应用于乳腺癌的诊断。其次，利用生物等电子理论，将谷氨酰胺的酰胺替换为氰基得到(2S, 4R)4-[18F]FCABA，其转运载体与谷氨酰胺类似，有望应用于肿瘤的诊断。第三，优化(2S, 4R)4-[18F]FGln的标记方法，设计合成了新的标记前体。该前体稳定性高，合成条件简单，解决了之前(2S, 4R)4-[18F]FGln标记前体的问题，有利于(2S, 4R)4-[18F]FGln进一步临床推广。最后，基于谷氨酰胺的设计经验之上，本项目设计了精氨酸代谢型PET显像剂(2S, 4S)4-[18F]FPArg，其转运载体的类型与精氨酸类似。其有望诊断精氨酸代谢相关的肿瘤进有望监测精氨酸剥夺的疗效。本项目研究计氨基酸的经验将为开发其它类型的显像剂提供设计参考。本项目研究的自主知识产权的显像剂进一步在临床验证中，有望为患者提供可靠的影像学诊疗依据并产生较大的经济效益。