Synthesis, Labeling, and Biological Evaluation of P2Y Receptor Radioligands for Positron Emission Tomography Imaging of Neuroinflammation.

The P2Y receptor (P2YR) 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 P2YR ligands and the radiolabeling and characterization of two positron emission tomography (PET) tracers, [C] and [F]. These compounds were evaluated by autoradiography studies on rat brain slices exhibiting overexpression of human P2YRs (AAV-P2YR). Metabolism and biodistribution of [F] 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-P2YR rat model confirmed this low brain uptake, and no significant difference was found in the transfected (SUV 0.14 ± 0.01) versus contralateral (SUV 0.13 ± 0.01) striatum of the AAV-P2YR 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 [F] brain concentration, suggesting that [F] is a P-glycoprotein substrate. Future work will focus on improving radioligand design to enhance blood-brain barrier permeation and to reduce efflux transport.