Among orexin receptor ligands, the unselective OXR antagonist suvorexant (Figure ) is the only FDA-approved drug used for the treatment of insomnia. However, the exact role of the OXR subtypes in the brain and in tumors is not well understood and requires further elucidation. Molecular imaging with positron emission tomography (PET) applying subtype-selective radioligands could be a very valuable and sensitive tool to achieve this goal. However, previous attempts to develop radioligands suitable for in vivo PET imaging of OX1R or OX2R have been unsuccessful. Most of these efforts addressed OX2R-selective PET ligand candidates (Figure ; [ 11 C]CW4 , [ 18 F]seltorexant , and others ), however, these studies reported low brain uptake, interaction with efflux transporters, or significant lack of specific binding in vivo. The OX1R-selective PET ligand candidates investigated so far faced the same challenges (Figure ), such that [ 18 F]THIQ derivatives showed low brain uptake due to poor pharmacokinetics , and [ 18 F]PBC-1 showed in vivo instability .