Exploring occupancy of the histamine H3 receptor by pitolisant in humans using PET.

ABSTRACT

BACKGROUND AND PURPOSE: BF2.649 (pitolisant, Wakix®) is a novel histamine H3 receptor inverse agonist/antagonist recently approved for the treatment of narcolepsy disorder. The objective of the study was to investigate in vivo occupancy of H3 receptors by BF2.649 using PET brain imaging with the H3 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 VND 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 H3 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 H3 receptors and may be a new tool for the treatment of a variety of CNS disorders that are associated with mechanisms involving H3 receptors.