神经突触功能改变与阿尔茨海默病（AD）认知障碍密切相关，本课题前期发现突触改变及衰亡可能是AD发生发展的重要环节。突触囊泡糖蛋白2A（SV2A）是突触的重要蛋白，可作为测量突触密度的生物标记物，同时突触的功能在AD病人的认知丢失中起着重要作用，修复突触的功能可改善AD病人的认知。本项目以SV2A PET探针11C-UCB-J和SV2A功能修复药物左乙拉西坦、UCB0255为先导化合物，设计合成系列新化合物，体外筛选SV2A亲和活性和SV2A突触前钙离子通道抑制活性并进行体内活性评价，以期获得适合临床转化的新型[18F] SV2A探针及AD早期干预候选药物。本项目以SV2A靶向的突触功能障碍为突破点，研制具有自主知识产权的正电子显像和早期干预候选药物，期望对AD临床诊断及治疗提供新方法，同时为临床治疗新靶点提供理论基础。

The loss of synapses is a consistent and robust pathology in Alzheimer’s disease (AD) and has been shown to be closely related to cognitive impairment and memory loss. However, the pathogenesis of cognitive impairment and the neural circuitry involved in the impairment of memory are yet to be fully understood. Based on results from our earlier work on the imaging investigation of β–amyloid (Aβ), we hypothesize that one of key events in AD pathophysiology is the toxic interactions between Aβ and synapses, leading to synaptic disruption and loss. The synaptic vesicle glycoprotein 2A (SV2A) is an integral glycoprotein located in the cell membrane of secretory vesicles, and has been shown to be a biomarker for synaptic density, At the same time, synaptic function plays an important role in cognitive loss of AD patients, repair of synaptic function can improve the cognitive function of AD patients. In this project we use the best SV2A PET radioligand, 11C-UCB-J, as lead structure, and to design and synthesize a series of compounds with high SV2A affinity, and use the SV2A functional repair drugs Levetiracetam and UCB0255 as lead compoound, to design and synthesize a series of compounds. SV2A affinity activity and SV2A presynaptic calcium channel inhibitory activity were screened in vitro and evaluated in vivo in order to obtain a novel 18F SV2A probe suitable for clinical transformation and candidate drugs for early intervention of AD. This project takes synaptic dysfunction targeted by SV2A as a breakthrough point, develops PET imaging probe and early intervention candidate drugs. It is expected to provide a new method for clinical diagnosis and treatment of early state of AD, as well as a theoretical basis for new clinical treatment targets.