Synthesis, preclinical evaluation and pilot clinical study of a P2Y12 receptor targeting radiotracer [18F]QTFT for imaging brain disorders by visualizing anti-inflammatory microglia

作者：Bolin Yao, Yanyan Kong, Jianing Li, Fei Xu, Yan Deng, Yuncan Chen, Y Chen, Jian Chen, Minhua Xu, Xiao Zhu, Liang Chen, Fang Xie, Xin Zhang, Cong Wang, Cong Li · 发表于：Acta Pharmaceutica Sinica B · 年份：2025 · DOI：10.1016/j.apsb.2025.01.009 · 被引用次数：10 · 研究领域：Adenosine and Purinergic Signaling、Nanoplatforms for cancer theranostics、Neuroinflammation and Neurodegeneration Mechanisms

As the brain's resident immune cells, microglia perform crucial functions such as phagocytosis, neuronal network maintenance, and injury restoration by adopting various phenotypes. Dynamic imaging of these phenotypes is essential for accessing brain diseases and therapeutic responses. Although numerous probes are available for imaging pro-inflammatory microglia, no PET tracers have been developed specifically to visualize anti-inflammatory microglia. In this study, we present an 18 F-labeled PET tracer (QTFT) that targets the P2Y 12 , a receptor highly expressed on anti-inflammatory microglia. [ 18 F]QTFT exhibited high binding affinity to the P2Y 12 (14.43 nmol/L) and superior blood–brain barrier permeability compared to other candidates. Micro-PET imaging in IL-4-induced neuroinflammation models showed higher [ 18 F]QTFT uptake in lesions compared to the contralateral normal brain tissues. Importantly, this specific uptake could be blocked by QTFT or a P2Y 12 antagonist. Furthermore, [ 18 F]QTFT visualized brain lesions in mouse models of epilepsy, glioma, and aging by targeting the aberrantly expressed P2Y 12 in anti-inflammatory microglia. In a pilot clinical study, [ 18 F]QTFT successfully located epileptic foci, showing enhanced radioactive signals in a patient with epilepsy. Collectively, these studies suggest that [ 18 F]QTFT could serve as a valuable diagnostic tool for imaging various brain disorders by targeting P2Y 12 overexpressed in anti-inflammatory microglia. ...