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.


University of Bari Aldo Moro, Italy, Coordinatore
Copenhagen University - Hospital Rigshosnitalet, Denmark, Partner
MJFF - 022329
Fall 2022 RF A: Novel PET Tracer Development Program
Michael J. Fox Foundation for Parkinson's Disease
$ 240.125,00
$ 74.750,00