Structure-Affinity-Pharmacokinetics Relationships of Novel 18F‑Labeled 1,4-Diazepane Derivatives for Orexin 1 Receptor Imaging

The orexin 1 receptor (OX1R) has been suggested to be involved in the reward and autonomic nervous systems. Positron emission tomography (PET) of OX1R contributes to elucidating its role and developing new drugs. However, there are no useful PET probes for in vivo imaging of OX1R. Here, we newly designed and synthesized 18F-labeled 1,4-diazepane derivatives and evaluated their utilities as OX1R PET probes. In particular, BTF showed high and selective binding affinity for OX1R. In a biodistribution study using normal mice, [18F]­BTF exhibited brain uptake, and radioactivity in the brain was significantly decreased by preinjection of unlabeled BTF. In a PET/CT study, it was suggested that [18F]­BTF has the potential to visualize high-expression regions of OX1R in the normal mouse brain. Collectively, [18F]­BTF has the fundamental features of an OX1R PET probe, and further studies may lead to the development of more useful probes.