Abstract

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 anF-labeled PET tracer (QTFT) that targets the P2Y, a receptor highly expressed on anti-inflammatory microglia. [F]QTFT exhibited high binding affinity to the P2Y(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 [F]QTFT uptake in lesions compared to the contralateral normal brain tissues. Importantly, this specific uptake could be blocked by QTFT or a P2Yantagonist. Furthermore, [F]QTFT visualized brain lesions in mouse models of epilepsy, glioma, and aging by targeting the aberrantly expressed P2Yin anti-inflammatory microglia. In a pilot clinical study, [F]QTFT successfully located epileptic foci, showing enhanced radioactive signals in a patient with epilepsy. Collectively, these studies suggest that [F]QTFT could serve as a valuable diagnostic tool for imaging various brain disorders by targeting P2Yoverexpressed in anti-inflammatory microglia.