A New Positron Emission Tomography Probe for Orexin Receptors Neuroimaging.

The orexin receptor (OX) is critically involved in motivation and sleep-wake regulation and holds promising therapeutic potential in various mood disorders. To further investigate the role of orexin receptors (OXRs) in the living human brain and to evaluate the treatment potential of orexin-targeting therapeutics, we herein report a novel PET probe ([C-11]CW24) for OXRs in the brain. CW24 has moderate binding affinity for OXRs (IC50 = 0.253 mu M and 1.406 mu M for OX1R and OX2R, respectively) and shows good selectivity to OXRs over 40 other central nervous system (CNS) targets. [C-11]CW24 has high brain uptake in rodents and nonhuman primates, suitable metabolic stability, and appropriate distribution and pharmacokinetics for brain positron emission tomography (PET) imaging. [C-11]CW24 warrants further evaluation as a PET imaging probe of OXRs in the brain.