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

Background And Purpose: BF2.649 (pitolisant, Wakix®) is a novel histamine H 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 receptors by BF2.649 using PET brain imaging with the H receptor antagonist radioligand [ C]GSK189254.

Experimental Approach: Six healthy adult participants were scanned with [ 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). [ 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 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 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 receptors and may be a new tool for the treatment of a variety of CNS disorders that are associated with mechanisms involving H receptors.