title: (11)C-MK-8278 PET as a tool for pharmacodynamic brain occupancy of histamine 3 receptor inverse agonists.
abstract: The histamine 3 (H3) receptor is a presynaptic autoreceptor in the central nervous system that regulates the synthesis and release of histamine and modulates the release of other major neurotransmitters. H3 receptor inverse agonists (IAs) may be efficacious in the treatment of various central nervous system disorders, including excessive daytime sleepiness, attention deficit hyperactivity disorder, Alzheimer disease, ethanol addiction, and obesity.
  
  
  METHODS
  Using PET and a novel high-affinity and selective radioligand (11)C-MK-8278, we studied the tracer biodistribution, quantification, and brain H3 receptor occupancy (RO) of MK-0249 and MK-3134, 2 potential IA drugs targeting cerebral H3 receptors, in 6 healthy male subjects (age, 19-40 y). The relationship among H3 IA dose, time on target, and peripheral pharmacokinetics was further investigated in 15 healthy male volunteers (age, 18-40 y) with up to 3 PET scans and 3 subjects per dose level.
  
  
  RESULTS
  The mean effective dose for (11)C-MK-8278 was 5.4 ± 1.1 μSv/MBq. Human brain kinetics showed rapid high uptake and fast washout. Binding potential values can be assessed using the pons as a reference region, with a test-retest repeatability of 7%. Drug RO data showed low interindividual variability per dose (mean RO SD, 2.1%), and a targeted 90% RO can be reached for both IAs at clinically feasible doses.
  
  
  CONCLUSIONS
  (11)C-MK-8278 is a useful novel PET radioligand for determination of human cerebral H3 receptor binding and allows highly reproducible in vivo brain occupancy of H3-targeting drugs, hereby enabling the evaluation of novel compounds in early development to select doses and schedules.
authors.affiliation: Division of Nuclear Medicine, University Hospital and KU Leuven, Leuven, Belgium.
authors.forename: Koenraad J
authors.initials: KJ
authors.lastname: Van Laere
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Sanabria-Bohórquez
authors.forename: David P
authors.initials: DP
authors.lastname: Mozley
authors.forename: Donald H
authors.initials: DH
authors.lastname: Burns
authors.forename: Terence G
authors.initials: TG
authors.lastname: Hamill
authors.forename: Anne
authors.initials: A
authors.lastname: Van Hecken
authors.forename: Inge
authors.initials: I
authors.lastname: De Lepeleire
authors.forename: Michel
authors.initials: M
authors.lastname: Koole
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
authors.forename: Jan
authors.initials: J
authors.lastname: de Hoon
authors.forename: Marleen
authors.initials: M
authors.lastname: Depré
authors.forename: Kristine
authors.initials: K
authors.lastname: Cerchio
authors.forename: John
authors.initials: J
authors.lastname: Plalcza
authors.forename: Lingling
authors.initials: L
authors.lastname: Han
authors.forename: John
authors.initials: J
authors.lastname: Renger
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hargreaves
authors.forename: Robert
authors.initials: R
authors.lastname: Iannone
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes / Q000494:pharmacology*; D017442:Histamine Agonists / Q000737:chemistry*; D006801:Humans; D021621:Imaging, Three-Dimensional; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000494:pharmacology*; D018100:Receptors, Histamine H3 / Q000737:chemistry*; D015203:Reproducibility of Results; D013141:Spiro Compounds / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001572:Benzofurans; D002250:Carbon Radioisotopes; D017442:Histamine Agonists; D008024:Ligands; C586679:MK-8278; D019275:Radiopharmaceuticals; D018100:Receptors, Histamine H3; D013141:Spiro Compounds
keywords: 11C-MK-8278; H3 receptor; PET; inverse agonist; kinetic modeling; receptor occupancy