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

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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.