新型NMDA受体分子探针与FMZ PET联合显像在精神分裂症谷氨酸功能异常致病机制中的研究

The imbalance between the two contrary excitatory glutamate-NMDAR system and inhibitory GABAergic pathway could be the pathogenesis of schizophrenia. NMDAR combined with GABAA/BZ PET imaging is expected to provide a new imaging biomarker for schizophrenia. There is no PET probes targeting NMDAR at present in China. Our project aims to carry out independent designs for novel NMDAR molecular probes on the basis of foreign researchers' work, by means of computer aided molecular design (CAMD) and in vitro and in vivo affinity-binding experiments. 2 or 3 novel compounds with excellent affinity and low toxicity for NMDAR are expected to be found. GABAA/BZ imaging tracer flumazenil (FMZ) labelled by 11C has already been developed by our center. NMDAR combined with 11C-FMZ PET imaging will be performed on the schizophrenia model mice, and PMOD software is meant for the semiquantitative analysis to evaluate the two receptors’ functional change on all brain regions, which would be complementary help for the in-vivo study of NMDAR and GABAA/BZ abnormality, to explore the glutamate dysfunction pathogenesis in schizophrenia.

兴奋性谷氨酸-NMDAR系统及抑制性GABA能之间的失衡可能是导致精神分裂症发病的两个重要方面. NMDAR及GABAA/BZ受体联合PET显像有望为精神分裂症提供一个新的影像学标志物。目前国内尚未有针对NMDAR的正电子探针，本项目拟在国外研究者的工作基础上，借助计算机辅助分子模拟手段，自主设计、合成新型NMDAR探针，并通过体内外活性测试筛选获得2-3个高效、低毒的新型NMDAR探针，同时采用本中心已成熟的GABAA/BZ受体探针11C-氟马西尼（FMZ），同新合成的NMDAR探针在精神分裂症模型鼠进行联合PET显像，使用PMOD软件分析量化各脑区受体功能的改变，从活体分子显像水平研究精神分裂症相应的受体功能改变，对谷氨酸功能异常致病机制作补充研究。

本项目以GE179为先导化合物，借助计算机辅助分子模拟手段，自主设计、合成新型靶向NMDAR化合物60个以并完成结构鉴定，通过体外活性测试已发现3个化合物的活性优于先导。利用华山医院的国产北京派特氟多功能合成模块成功放射标记合成了18F-GE-179，并将其制剂通过了华山医院检验科的注射剂检查，达到了人体注射水平，这是国内是首次实现该药物的生产并能达到注射水平，丰富了华山医院PET中心的诊断特药品种。该药物在活体动物水平已进行了靶点验证，证明该药可以进行NMDAR高表达诊断。完善了11C-FMZ的标记工艺，稳定的工艺使得目前11C-FMZ已在华山医院PET中心应用于临床，该检查已成为华山医院神经外科（全国排名前二）癫痫手术的常规定位诊断项目，该药物的开发和稳定为医院的临床用药提供了很大保障。在项目的支持下已经发表了3篇SCI论文，申请专利两项，协助培养博士研究生2名，硕士研究生1名。