Structure-guided discovery of orexin receptor-binding PET ligands

Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into the expression pattern and the in vivo imaging of the G protein-coupled orexin receptors OX1R and OX2R will further our understanding of the orexin system and its role in various physiological and pathophysiological processes. Guided by crystal structures of our lead compound JH112 and the approved hypnotic drug suvorexant bound to OX1R and OX2R, respectively, we herein describe the design and synthesis of two novel radioligands, [¹⁸F]KD23 and [¹⁸F]KD10. Key to the success of our structural modifications was a bioisosteric replacement of the triazole moiety with a fluorophenyl group. The ¹⁹F-substituted analog KD23 showed high affinity for the OX1R and selectivity over OX2R, while the high affinity ligand KD10 displayed similar K_i values for both subtypes. Radiolabeling starting from the respective pinacol ester precursors resulted in excellent radiochemical yields of 93% and 88% for [¹⁸F]KD23 and [¹⁸F]KD10, respectively, within 20 min. The new compounds will be useful in PET studies aimed at subtype-selective imaging of orexin receptors in brain tissue.