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

Orexin 2 receptors (OXR) 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 OXR in vivo. Herein, we report [C] ([C]OX-2201) and [C] ([C]OX-2202) as novel PET ligands. Both compounds ( = 3.6 nM) and ( = 2.2 nM) have excellent binding affinity activities toward OXR and target selectivity (OX/OX > 600 folds). autoradiography in the rat brain suggested good to excellent binding specificity for [C] and [C]. PET imaging in rat brains indicated that the low brain uptake of [C] 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.