Pablo Rusjan1,2,3, Pamela Sabioni4, Patricia Di Ciano2,4,5,3, Esmaeil Mansouri1,6, Isabelle Boileau1,3,7, Alexia Laveillé8, Marc Capet8, Thierry Duvauchelle8, Jean-Charles Schwartz9, Philippe Robert9, Bernard Le Foll1,10,3,11,7. 1. Research Imaging Centre, CAMH, Toronto, Canada. 2. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada. 3. Campbell Family Mental Health Research Institute, CAMH, Toronto, Canada. 4. Translational Addiction Research Laboratory, CAMH, Toronto, Canada. 5. Institute for Mental Health Policy Research, CAMH, Toronto, Canada. 6. Institute of Medical Sciences, University of Toronto, Toronto, Canada. 7. Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Canada. 8. Bioprojet Pharma, Paris, France. 9. Bioprojet Biotech, Paris, France. 10. Acute Care Program, CAMH, Toronto, Canada. 11. Department of Family and Community Medicine, University of Toronto, Toronto, Canada.
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.
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.
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