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

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.