Syntheses and preclinical evaluations of C-labeled radioligands for imaging brain orexin-1 and orexin-2 receptors with positron emission tomography.

Despite their importance in regulating several functions in the brain, there is no effective radioligand for imaging of brain orexin-1 (OXR) or orexin-2 receptors (OXR) with positron emission tomography (PET). In a search for radioligand candidates, we identified GSK1059865 (1) as a highly potent and selective inhibitor for OXR ( = 5.0 nM for OXR, ∼80-fold selective over OXR) and similarly ET1 (2) for OXR (IC = 0.8 nM for OXR, ∼3000-fold selective over OXR) with each possessing many physicochemical properties conducive for good brain permeability. We labeled compound 1 and compound 2 with carbon-11 ( = 20.4 min) in high isolated yields (∼10-20%), radiochemical purities (≥99.5%), and molar activities (100-340 GBq μmol) and assessed their potential as PET radioligands for imaging of brain OXR and OXR in healthy rodents and non-human primates. [C]1 and [C]2 showed excellent stability and also lipophilicity in a desirable range with measured log values of 3.69 and 2.90, respectively. After intravenous administration to mouse or monkey, both [C]1 and [C]2 gave moderately high peak radioactivity in brain (∼1.0-1.6 SUV). Unexpectedly, both [C]1 and [C]2 showed slightly lower monkey brain uptakes and distribution volumes at baseline than under blocking with suvorexant (a dual OXR/OXR antagonist), indicating a lack of specific binding to the target receptors in healthy animals. We infer that both OXRs exist in healthy mouse and monkey brain at very low density. Animal models, where OXR and OXR levels might be elevated, are desirable for candidate PET radioligand development, as are candidates with higher affinity.