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

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.

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.

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.

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.