混合型氨基酸转运体分子探针的构建及联合MET在脑胶质瘤精准成像中的应用研究

Amino acid transporter molecular probe combined with PET imaging provides a key molecular imaging information for the diagnosis and treatment of glioma，however, the clinically applied tracers can not give sufficient information for accurate definition and staging. Our preliminary study showed that the specificity of MET was as high as 99%, while the sensitivity was only 85%, which is insufficient for the glioma staging. To overcome this deficit, the current study plans to use (S)-[18F]FAMPe as the lead compound, and combine the advantges of both L-type tracers (good blood-brain-barrier permeability) and A/ASC-type tracers (high target-to background ratio). With the aid of computer-assisted drug design to analyze the structure-activity relationship of target compound, we plan to develop a mixed amino acid transporter molecular probe with higher sensitivity for preclinical experiments. Meanwhile, the joint imaging of MET and our new molecular probe combined the advantage of high specificity of L-type probe and high sensitivity of mixed-type probe, thus providing a new approach for the precise imaging and early diagnosis and treatment of glioma. The research on the development and joint imaging of the new molecular probe plays a pivotal role in the staging and treatment of glioma, especially in determining the scope of precise excision.

氨基酸转运体分子探针联合PET显像为胶质瘤的诊治提供了关键的分子功能影像学信息，然而，目前临床上使用的显像剂还存在划定肿瘤浸润范围不精确，分级不明晰等缺陷。我们前期研究显示L-型氨基酸转运体显像剂MET对胶质瘤的特异性为99%，但分级诊断，灵敏度不够（85%），针对L-型显像剂灵敏度相对不足，本项目将以(S)-[18F]FAMPe为先导化合物，借助计算机辅助药物设计，结合血脑屏障通透性好的L-型和高靶本比的A-型/ASC-型氨基酸显像剂的结构和功能优势，深入目标分子构效关系研究，开发灵敏性更高的混合型氨基酸转运体分子探针，进行临床前相关研究。同时探讨新探针分子与MET联合显像，高特异性的L-型和高灵敏性的混合型分子探针优势互补，为胶质瘤精准成像，早期诊治提供新的方法。新探针分子的开发和联合显像模式的研究，对于脑胶质瘤的分级诊断和治疗，尤其是手术精准切除范围具有重要的临床指导意义。

氨基酸转运体分子探针联合PET显像为胶质瘤的诊治提供了关键的分子功能影像学信息，然而，目前临床上使用的显像剂还存在划定肿瘤浸润范围不精确，分级不明晰等缺陷。本项目开展了三方面的研究：1、设计完成了30个具有自主知识产权的新化合物，并进行了化学合成和结构鉴定，为开发新型混合氨基酸分子探针提供有力的保证。2、完成L-型氨基酸转运体11C-MET放射标记合成、质控，开展了近200例临床胶质瘤病人PET显像并建立了数据库，为胶质瘤术前分级判断和IDH1基因突变的预测提供了重要的价值。3、开发了18-氟标L-型氨基酸转运体18F-FET的标记合成，开展了临床前药学安全性评价和DBT胶质瘤小动物PET显像，顺利通过了医院伦理委员会的药物临床试验申请，近三年完成了近800例临床胶质瘤病人显像，为医院神经外科胶质瘤术前诊断提供了宝贵的影像学数据，同时通过对大量病人样本的异质性参数分析，提高胶质瘤病例的分级诊断和异柠檬酸脱氢酶（IDH1）突变状态的预测效能。大量临床病人影像数据库的建立，为胶质瘤的术前分级诊断提供了可靠的依据。