title: Human Kinetic Modeling of the 5HT6 PET Radioligand 11C-GSK215083 and Its Utility for Determining Occupancy at Both 5HT6 and 5HT2A Receptors by SB742457 as a Potential Therapeutic Mechanism of Action in Alzheimer Disease.
abstract: Antagonism of 5-hydroxytrypamine-6 (5HT6) receptors is associated with procognitive effects in preclinical species, suggesting a therapeutic potential for this mechanism in Alzheimer disease (AD) and other cognitive diseases. In a phase 2 dose study, SB742457, a novel 5HT6 antagonist, showed increasing procognitive effects in patients with AD as the dose increased, with a procognitive signal in AD patients at a dose of 35 mg/d superior to the other doses tested (5 and 15 mg/d).
  
  
  METHODS
  In this article, we describe the quantification and pharmacologic selectivity of a new 5HT6 PET ligand ((11)C-GSK215083) in healthy volunteers and its use to measure occupancies achieved at various doses of SB742457.
  
  
  RESULTS
  Kinetic analysis of (11)C-GSK215083 uptake in the human brain demonstrated the multilinear model, MA2, to represent the method of choice when a blood input was available and the full tissue reference method when no input was available. Pharmacologic dissection of the in vivo (11)C-GSK215083-specific binding showed the ligand bound mostly the 5HT6 in the striatum (blocked by SB742457 but not by the selective 5-hydroxytryptamine-2A (5HT2A) antagonist ketanserin) and the 5HT2A in the frontal cortex (blocked by both ketanserin and SB742457). Repeated administration of SB742457 (3, 15, and 35 mg/d) saturated the 5HT6 receptors at all doses. In the cortex, 5HT2A receptor occupancy was 24% ± 6% (3 mg/d), 35% ± 4% (15 mg/d), and 58% ± 19% (35 mg/d; mean ± SD), suggesting a progressive engagement of 5HT2A as the dose increased.
  
  
  CONCLUSIONS
  Collectively, these data support the use of (11)C-GSK215083 as a 5HT6 clinical imaging tool and suggest that blocking both the 5HT6 and the 5HT2A receptors may be required for the optimal therapeutic action of SB742457 in AD.
authors.affiliation: GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, United Kingdom Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom Christine.A.Parker@gsk.com.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Parker
authors.affiliation: Imanova Ltd., Imperial College London, London, United Kingdom Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, United Kingdom.
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom Imanova Ltd., Imperial College London, London, United Kingdom Department of Engineering Science, University of Oxford, Oxford, United Kingdom.
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Searle
authors.affiliation: AbbVie, Translational Imaging, Integrated Science and Technology, North Chicago, Illinois.
authors.forename: Laurent
authors.initials: L
authors.lastname: Martarello
authors.affiliation: Roche Pharmaceutical Research and Early Development, Basel, Switzerland.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Comley
authors.affiliation: GlaxoSmithKline, Neuroscience Therapy Area Unit, Stevenage, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Davy
authors.affiliation: Research Imaging Centre, CAMH, and Department of Psychiatry, University of Toronto, Toronto, Canada.
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.affiliation: Research Imaging Centre, CAMH, and Department of Psychiatry, University of Toronto, Toronto, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.affiliation: Research Imaging Centre, CAMH, and Department of Psychiatry, University of Toronto, Toronto, Canada.
authors.forename: Romina
authors.initials: R
authors.lastname: Mizrahi
authors.affiliation: Intra-Cellular Therapies Inc., New York, New York; and.
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
authors.affiliation: School of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Cunningham
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000188:drug therapy*; D001923:Brain Chemistry / Q000187:drug effects; D005260:Female; D006801:Humans; D007553:Isotope Labeling; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D015203:Reproducibility of Results; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013450:Sulfones / Q000493:pharmacokinetics*
chemical_list: C548140:3-benzenesulfonyl-8-piperazin-1-ylquinoline; C571031:GSK215083; D011804:Quinolines; D019275:Radiopharmaceuticals; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013450:Sulfones; C097216:serotonin 6 receptor
keywords: 11C-GSK215083; 5HT6; Alzheimer’s disease; SB742457; human kinetic modeling