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

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 ¹⁸F-labeled PET tracer (QTFT) that targets the P2Y₁₂, a receptor highly expressed on anti-inflammatory microglia. ¹⁸FQTFT exhibited high binding affinity to the P2Y₁₂ (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 ¹⁸FQTFT uptake in lesions compared to the contralateral normal brain tissues. Importantly, this specific uptake could be blocked by QTFT or a P2Y₁₂ antagonist. Furthermore, ¹⁸FQTFT visualized brain lesions in mouse models of epilepsy, glioma, and aging by targeting the aberrantly expressed P2Y₁₂ in anti-inflammatory microglia. In a pilot clinical study, ¹⁸FQTFT successfully located epileptic foci, showing enhanced radioactive signals in a patient with epilepsy. Collectively, these studies suggest that ¹⁸FQTFT could serve as a valuable diagnostic tool for imaging various brain disorders by targeting P2Y₁₂ overexpressed in anti-inflammatory microglia.