Synthesis and characterization of a new Positron emission tomography probe for orexin 2 receptors neuroimaging.

The orexin receptors (OXRs) have been involved in multiple physiological and neuropsychiatric functions. Identification of PET imaging probes specifically targeting OXRs enables us to better understand the OX system. Seltorexant (JNJ-42847922) is a potent OXR antagonist with the potential to be an OXR PET imaging probe. Here, we describe the synthesis and characterization of [F]Seltorexant as an OXR PET probe. The ex vivo autoradiography studies indicated the good binding specificity of [F]Seltorexant. In vivo PET imaging of [F]Seltorexant in rodents showed suitable BBB penetration with the highest brain uptake of %ID/cc = 3.4 at 2 min post-injection in mice. The regional brain biodistribution analysis and blocking studies showed that [F]Seltorexant had good binding selectivity and specificity. However, pretreatment with unlabelled Seltorexant and P-gp competitor CsA observed significantly increased brain uptake of [F]Seltorexant, indicating [F]Seltorexant could interact P-gp at the blood-brain barrier. Our findings demonstrated that [F]Seltorexant is a potential brain OXR PET imaging probe, which paves the way for new OXR PET probes development and OX system investigation.