转位蛋白18 kDa（TSPO）多态性非敏感PET探针研发及其在AD炎症机制中的初步探索

神经炎症是目前AD研究的重要方向之一，TSPO是神经炎症的重要生物标志物，基于该靶点PET成像对深入探索AD炎性机制意义重大，但目前临床缺少稳定且多态性非敏感的TSPO-PET探针。前期，申请人利用自主研发的SCIDY方法实现了TSPO高亲和力新型配体LW-1-F的18F标记，啮齿类动物初步影像研究显示该探针虽体内特异性较低，但过脑量高、洗脱快、多态性敏感度较弱，有进一步优化的潜力。本项目将以LW-1-F为先导化合物，首先利用药物化学手段围绕新型芳香氟类喹啉氧连酰胺骨架建立配体库、探讨活性及敏感度与杂环结构的关系，筛选目标分子；之后利用SCIDY进行18F标记，综合免疫染色、放射自显影、PET分子影像、恒河猴脑动力学模拟实现定量表征，旨在发展一种进脑量高、结构稳定、特异性强且TSPO多态性非敏感PET探针，初步探讨新型探针在AD模型鼠脑内的炎性显像，为AD神经炎症机制的研究提供科学依据。

TSPO is a critical biomarker of neuroinflammation, which plays an important role in the pathogenesis of Alzheimer’s disease (AD), accordingly, PET imaging of TSPO would pave a way for evaluation of neuro-inflammatory mechanism underlying AD. However, by now there is a lack of stable and rs6971 polymorphism-insensitive TSPO-PET radioligand in clinical setting. In the early stage, we realized the 18F-labeling of a novel ligand namely LW-1-F with high affinity to TSPO. Preliminary PET imaging of rat brain demonstrated that although the specificity was relatively low, this tracer possessed high brain penetration, rapid washout, and low sensitivity to rs6971 polymorphism, which made worthy of further study of this scaffold. In this project, we plan to use LW-1-F as a lead compound, firstly, we will design and synthesize a ligand library by means of medicinal chemistry based on an aromatic fluoroquinazoline oxycarbamide moiety to explore the relationship between affinity/sensitivity and the heterocyclic structures, and screen the target molecules for labeling; then, we will test the capability for SCIDY-mediated radiofluorination, followed by immunostaining, autoradiography, microPET imaging for radioligand optimization, and further translate into non-human primate to achieve quantitative characterization such as distribution volume (VT) and binding potential (BPND) via kinetic modeling. This study aims to develop a stable TSPO polymorphism-insensitive PET radioligand with high specificity, which would be applied to the preliminary neuroimaging of AD mouse models, and provide a scientific basis for the study of neuro-inflammatory mechanism underlying AD.