Selective, Non-nucleotidic Radiotracer for P2Y12 Receptors: Design, Synthesis, Characterization, and Imaging of Brain Slices

  • J Med Chem. 2025 Jun 12;68(11):11279-11298. doi: 10.1021/acs.jmedchem.5c00213.
Haneen Al-Hroub  1 ,  Hashem Ali M Al Musawi  1 ,  Aliaa Abdelrahman  1 ,  Vigneshwaran Namasivayam  1 ,  Margot Corbel  2 ,  Fanny Petit  2 ,  Gunes Aksiyote  2 ,  Fabrice Beau  2 ,  Caroline Jan  2 ,  Alexis-Pierre Bemelmans  2 ,  Nadja Van Camp  2 ,  Marie-Anne Peyronneau  3 ,  Alexandra Winkeler  3 ,  Christa E Müller  1
Affiliations
  • 1. PharmaCenter Bonn, Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, Germany.
  • 2. Laboratoire des Maladies Neurodégénératives, CEA, CNRS, MIRCen, Université Paris-Saclay, Fontenay-aux-Roses 92265, France.
  • 3. Laboratoire d'Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Université Paris-Saclay, Orsay 91401, France.
PMID: 40367388 DOI: 10.1021/acs.jmedchem.5c00213
Abstract

The G protein-coupled, ADP-activated P2Y12 receptor (P2Y12R) expressed by microglial cells is involved in neuroinflammation constituting a promising biomarker. Here, we designed and characterized a potent and selective non-nucleotidic P2Y12-antagonist radioligand, [3H]PSB-22219 ([3H]18). The unlabeled compound was stable in rat liver microsomes and selective versus Other ADP-activated receptors. [3H]18 displayed high-affinity binding to membrane preparations recombinantly expressing the human P2Y12R (KD = 4.57 nM), showing very low nonspecific binding. Radioligand binding assays were established and employed to characterize P2Y12Rs natively expressed in human platelet (KD = 2.53 nM), rat brain cortex (KD = 5.35 nM), and mouse microglial cell preparations (KD = 269 nM), with microglia showing extraordinarily high P2Y12R expression. Autoradiography studies allowed the visualization of human P2Y12R overexpression in the brain of a humanized rat model. The new radioligand is expected to become a useful pharmacological tool that will contribute to the development of therapeutics and radiodiagnostics targeting brain P2Y12Rs.

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