Development of radiotracers targeting PURInoreceptor P2Y12, a promising target for positron emission tomography (PET) imaging of neuroinflammation

神经退行性（ND）和神经系统疾病诱导中枢神经系统（CNS）内的神经炎症反应，以限制疾病的程度并支持修复和再生。为了监测和跟踪体内的神经炎症，靶向小胶质细胞作为中枢神经系统的常驻免疫细胞和神经炎症反应的关键参与者，是正电子发射断层扫描（PET）成像的主要焦点。我们提出，核苷酸（ADP）激活的G蛋白偶联P2Y12受体（一种稳态和抗炎小胶质细胞的标记物）的配体将是小胶质细胞活性成像的理想候选者。PURImaging项目提出了针对P2Y12受体的新型脑渗透PET示踪剂的开发和验证。PURImaging的主要目标是1。开发新的脑渗透配体，以高亲和力和选择性特异性靶向P2Y12受体，2。表征P2Y12受体配体的代谢稳定性、中枢神经系统生物利用度及其特异性结合；3 .用18F或11C放射性标记有希望的P2Y12受体候选配体，并在体内进行验证；应用它们来测定ND疾病动物模型和ND疾病患者死后组织中P2Y12受体的表达。

Neurodegenerative (ND) and neurological disorders induce a neuroinflammatory response within the central nervous system (CNS) in order to limit the extent of the disease and to support repair and regeneration. In order to monitor and follow neuroinflammation in vivo, targeting of microglia, the CNS resident immune cells and key-players in the neuroinflammatory response, are a major focus in positron emission tomography (PET) imaging. We propose that ligands of the nucleotide-(ADP)-activated G protein-coupled P2Y12 receptor, a marker for homeostatic and anti-inflammatory microglia, will be ideal candidates for imaging of microglial activity. The PURImaging project proposes the development and validation of novel and brain permeable PET tracers targeting the P2Y12 receptor.The main objectives of PURImaging are to1. develop novel brain penetrant ligands that specifically target the P2Y12 receptor with high affinity and selectivity,2. characterize P2Y12 receptor ligands for their metabolic stability, CNS bioavailability and their specific binding,3. radiolabel promising P2Y12 receptor candidate ligands with 18F or 11C, and validate them in vivo, and4. apply them to determine P2Y12 receptor expression in animal models of ND diseases and in human post-mortem tissues of patients with ND disease.