PURImaging – Development of radiotracers targeting PURInoreceptor P2Y12, a promising target for positron emission tomography (PET) imaging of neuro-inflammation – PURImaging

Neurodegenerative 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. However, various disease mechanisms may lead to harmful chronic neuro-inflammation contributing to the disease process itself and promoting disease progression. Microglia are resident immune cells of the CNS. Depending on their activation status, microglia response can be detrimental or beneficial. Due to their implication and their strong responsiveness during inflammation, activated microglia have become a major focus for the quantitative localization of neuroinflammation by imaging. The nucleotide-(ADP)-activated G protein-coupled P2Y12 receptor, a marker for homeostatic and anti-inflammatory microglia, has been identified as an imaging target of choice for positron emission tomography (PET) to enable monitoring of microglia in their anti-inflammatory state in vivo. However, the first promising radioligand developed, which showed high P2Y12 receptor affinity, did not cross the blood-brain-barrier (BBB). The PURImaging project proposes the development and validation of novel PET tracers targeting the P2Y12 receptor, which are able to cross the blood-brain-barrier.
The main objectives of PURImaging are to

1. 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, and
4. apply them to determine P2Y12 receptor expression in animal models of ND diseases and in human post-mortem tissues of patients with ND disease.

This research program shall allow the selection and radiolabeling of at least one preclinical drug candidate targeting the P2Y12 receptor with optimal PET characteristics. To make these objectives a reality, a French-German collaborative team has been established between the BioMaps unit at the Service Hospitalier Frédéric Joliot (CEA) and the Pharmazeutisches Institut at the Bonn University. Such a PET tracer may be translated into clinical studies and will be of high importance to understand microglia functions in the various diseases associated with neuroinflammation, and during the course of the diseases. Diagnostic imaging will not only be useful for elucidating the role of microglia in inflammatory processes of the brain but also to monitor therapeutic interventions.