Exploring occupancy of the histamine H 3 receptor by pitolisant in humans using PET

Background and Purpose BF2.649 (pitolisant, Wakix®) is a novel histamine H 3 receptor inverse agonist/antagonist recently approved for the treatment of narcolepsy disorder. The objective of the study was to investigate in vivo occupancy of H 3 receptors by BF2.649 using PET brain imaging with the H 3 receptor antagonist radioligand [ 11 C]GSK189254. Experimental Approach Six healthy adult participants were scanned with [ 11 C]GSK189254. Participants underwent a total of two PET scans on separate days, 3 h after oral administration of placebo or after pitolisant hydrochloride (40 mg). [ 11 C]GSK189254 regional total distribution volumes were estimated in nine brain regions of interest with the two tissue‐compartment model with arterial input function using a common V ND across the regions. Brain receptor occupancies were calculated with the Lassen plot. Key Results Pitolisant, at the dose administered, provided high (84 ± 7%; mean ± SD) occupancy of H 3 receptors. The drug was well‐tolerated, and participants experienced few adverse events. Conclusion and Implications The administration of pitolisant (40 mg) produces a high occupancy of H 3 receptors and may be a new tool for the treatment of a variety of CNS disorders that are associated with mechanisms involving H 3 receptors.