Starting from the non-subtype-selective lead suvorexant, we successfully developed the OX1R-subtype-selective antagonist JH112 (Figure ) through the targeted application of docking methods, crystallography, medicinal chemistry, and in vitro pharmacology . JH112 showed subnanomolar binding affinity to the OX1R (Ki = 0.72 nM), while the affinity for the OX2R was 75-fold lower, making JH112 an excellent lead for the development of OX1R-selective PET ligands.