Development of Novel (11)C-Labeled Selective Orexin-2 Receptor Radioligands for Positron Emission Tomography Imaging

[Image: see text] Orexin 2 receptors (OX(2)R) represent a vital subtype of orexin receptors intricately involved in the regulation of wakefulness, arousal, and sleep–wake cycles. Despite their importance, there are currently no positron emission tomography (PET) tracers available for imaging the OX(2)R in vivo. Herein, we report [(11)C]1 ([(11)C]OX(2)-2201) and [(11)C]2 ([(11)C]OX(2)-2202) as novel PET ligands. Both compounds 1 (K(i) = 3.6 nM) and 2 (K(i) = 2.2 nM) have excellent binding affinity activities toward OX(2)R and target selectivity (OX(2)/OX(1) > 600 folds). In vitro autoradiography in the rat brain suggested good to excellent in vitro binding specificity for [(11)C]1 and [(11)C]2. PET imaging in rat brains indicated that the low brain uptake of [(11)C]2 may be due to P-glycoprotein and/or breast cancer resistance protein efflux interaction and/or low passive permeability. Continuous effort in medicinal chemistry optimization is necessary to improve the brain permeability of this scaffold.