Work

Synthesis, Labeling, and Biological Evaluation of P2Y12 Receptor Radioligands for Positron Emission Tomography Imaging of Neuroinflammation

Year: 2025

Type: article

Abstract: The P2Y 12 receptor (P2Y 12 R) is a G-protein-coupled receptor whose expression level is directly correlated to microglial activation. Herein, we report on the design of a series of new P2Y 12 R ligands and the radiolabeling and characterization of two positron emission tomography (PET) tracers, [ 11 C] 37 and [ 18 F] 41 . These compounds were evaluated by autoradiography studies on rat brain slices exhibiting overexpression of human P2Y 12 Rs (AAV- h P2Y 12 R). Metabolism and biodistribution of [ 18 F] 41 were evaluated ex vivo in healthy rats and indicated good metabolic stability with 41% of unchanged radioligand 1 h post injection and a limited crossing of the blood–brain barrier with a brain uptake of 0.02%ID/g 1 h post injection. In vivo PET imaging performed in the AAV- h P2Y 12 R rat model confirmed this low brain uptake, and no significant difference was found in the transfected (SUV mean 0.14 ± 0.01) versus contralateral (SUV mean 0.13 ± 0.01) striatum of the AAV- h P2Y 12 R model. Similar results were observed in healthy rats and in nonhuman primates. Additional studies in the presence of tariquidar led to a 3–4-fold increase in the [ 18 F] 41 brain concentration, suggesting that [ 18 F] 41 is a P-glycoprotein substrate. Future work will focus on improving radioligand design to enhance blood–brain barrier permeation and to reduce efflux transport.

Source: ACS Chemical Neuroscience

DOI: 10.1021/acschemneuro.5c00187