Funding from Michael J. Fox Foundation
- Published: Wednesday, 07 December 2022 11:22
- Hits: 186
The total project grant is worth 240.125 USD, and of these 74.025 USD go to NRU.
Abstract: Neuroinflammation plays a pivotal role in the pathogenesis of neurodegeneration in Parkinson's Disease(PD) through the upregulation of proinflammatory factors and microglia activation. The purinergic P2X7 receptor (P2X7R) is among the targets actively investigated as PET biomarkers of neuroinflammation because of its crucial role in microglia activation and expression associated with the M1 proinflammatory activation phenotype. Several potential P2X7R PET radioligands have been investigated during the last decade, but they show poor metabolic stability or low brain uptake in preclinical models. The only P2X7R PET radiotracer evaluated in PD patients so far - [11C]JNJ54173717 - failed to discriminate between PD and healthy individuals because of genotypic effects. This project aims at identifying an effective fluorine-18 radiotracer for imaging P2X7R in the CNS by carefully addressing the weakness featured by previous P2X7R PET radiotracer candidates. Our starting point will be three different chemotypes showing the promise for high P2X7R potency and selectivity, tunable physicochemical parameters to fit the characteristic of a PET radioligand, and ease of radionuclide incorporation. The newly developed P2X7R radiotracer(s) will be first evaluated in a microPET study on the LPS-treated rodent model to assess the in vivo specificity, then in ex vivo autoradiography on human cortical samples from PD patients. This latter evaluation will be performed side-by-side with [3H]JNJ-64413739, one of the most promising P2X7R radioligand identified so far, by considering the patients' genotype and the binding properties of the radiotracers. If successful, this project will identify an effective P2X7R PET radiotracer and ultimately contribute to advancing the knowledge on the role of neuroinflammation in PD.