Ketanserin exhibits dose- and concentration-proportional serotonin 2A receptor occupancy in healthy individuals: Relevance for psychedelic research.

Autor: Holze F; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark., Madsen MK; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark., Svarer C; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark., Gillings N; PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark., Stenbaek DS; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark; Department of Psychology, University of Copenhagen, Copenhagen, Denmark., Rudin D; Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland., Duthaler U; Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland., Liechti ME; Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland., Fisher PM; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Knudsen GM; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address: gmk@nru.dk.
Jazyk: angličtina
Zdroj: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology [Eur Neuropsychopharmacol] 2024 Nov; Vol. 88, pp. 43-48. Date of Electronic Publication: 2024 Aug 09.
DOI: 10.1016/j.euroneuro.2024.07.003
Abstrakt: The serotonin 2A (5-HT2A) receptor is an important target for drug development and the main receptor through which classical psychedelics elucidate their hallucinogenic effects. The 5-HT2A receptor antagonist ketanserin has frequently been used as a tool to block the receptor. Here, we establish the dose-occupancy relation of ketanserin and the cerebral 5-HT2A receptor in healthy participants by conducting a positron emission tomography (PET) study. 120-min PET scans using the 5-HT2A receptor agonist radiotracer [ 11 C]Cimbi-36 were conducted at baseline and after oral doses of either 10, 20, or 40 mg of ketanserin; each participant underwent one or two scans after ketanserin administration. Occupancy was defined as the percent change in neocortex binding potential (BP ND ), estimated using the simplified reference tissue model (SRTM) with the cerebellum as reference region. Peroral ketanserin intake resulted in a plasma concentration-related increase in cerebral 5-HT2A receptor occupancy with the highest plasma ketanserin concentrations measured after ∼2 h. The relation between mean plasma ketanserin concentrations and 5-HT2A receptor occupancy conformed to a single-site binding model with an estimated EC 50 (95 % CI) of 2.52 (0.75; 8.1) ng/mL, which corresponds to a peroral dose of ketanserin of approximately 10 mg. These data elucidate for the first time in humans the cerebral pharmacodynamics of ketanserin, both benefitting its use as a pharmacological tool for probing brain function and adding to its potential for therapeutic use in rescuing a bad psychedelic experience.
Competing Interests: Declaration of competing interest MKM has received an honorarium as a speaker for Lundbeck Pharma and the Lundbeck Foundation. DSS has received an honorarium as a speaker for the Lundbeck Foundation. MEL is a consultant for Mind Medicine, Inc. GMK has received honoraria as a speaker for Compass Ltd. and H. Lundbeck and is a consultant for Onsero, Pangea, and Gilgamesh, PureTechHealth, and is a board member of Elsass Foundation. All other authors declare no conflicts of interest.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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