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

开发针对 PURI 受体 P2Y12 的放射性示踪剂，这是神经炎症正电子发射断层扫描 (PET) 成像的一个有前景的靶标

• 批准号: 471773752
• 负责人: Professorin Dr. Christa E. Müller
• 金额: --
• 依托单位: Institut des sciences du vivant Frédéric Joliot
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/471773752?language=en
• 关键词: Development; radiotracers; targeting; PURInoreceptor; P2Y12

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.

神经退行性疾病（ND）和神经系统疾病在中枢神经系统（CNS）内诱导神经炎症反应，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神经炎症，靶向小胶质细胞，CNS驻留免疫细胞和神经炎症反应中的关键参与者，是正电子发射断层扫描（PET）成像的主要焦点。我们建议，配体的核苷酸（ADP）激活的G蛋白偶联P2 Y12受体，标志着自我平衡和抗炎小胶质细胞，将是理想的候选人小胶质细胞活性成像。PURImaging项目旨在开发和验证针对P2 Y12受体的新型脑渗透性PET示踪剂。开发特异性靶向P2 Y12受体且具有高亲和力和选择性的新型脑渗透配体; 2.表征P2 Y12受体配体的代谢稳定性、CNS生物利用度及其特异性结合，3.用18 F或11 C放射性标记有希望的P2 Y12受体候选配体，并在体内验证它们，和4.应用它们来确定P2 Y12受体在ND疾病的动物模型和患有ND疾病的人死后组织中的表达。