title: Imaging cortical dopamine D1 receptors using [11C]NNC112 and ketanserin blockade of the 5-HT 2A receptors.
abstract: [(11)C]NNC112 (8-chloro-7-hydroxy-3-methyl-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-IH-3-benzazepine), a selective positron-emission tomography (PET) ligand for the D(1) receptor (R) over the 5-HT(2A) R in vitro, has shown lower selectivity in vivo, hampering measurement of D(1) R in the cortex. [(11)C]NNC112 PET and intravenous (i.v) ketanserin challenge were used to (1) confirm the previous findings of [(11)C]NNC112 in vivo D(1) R selectivity, and (2) develop a feasible methodology for imaging cortical D(1) R without contamination by 5-HT(2A) R. Seven healthy volunteers underwent [(11)C]NNC112 PET scans at baseline and after a 5-HT(2A) R-blocking dose of ketanserin (0.15 mg/kg, i.v.). Percent BP(ND) change between the post-ketanserin and baseline scans was calculated. Irrespective of the quantification method used, ketanserin pretreatment led to significant decrease of BP(ND) in the cortical (approximately 30%) and limbic regions (approximately 20%) but not in the striatum, which contains a much lower amount of 5-HT(2A) R. Therefore, ketanserin allows D(1) R signal to be detected by [(11)C]NNC112 PET without significant 5-HT(2A) R contamination. These data confirm the presence of a significant 5-HT(2A) R contribution to cortical [(11)C]NNC112 signal, and call for caution in the interpretation of published [(11)C]NNC112 PET findings on cortical D(1) R in humans. In the absence of more selective ligands, [(11)C]NNC112 PET with ketanserin can be used for cortical D(1) R imaging in vivo.
authors.affiliation: Discovery Medicine, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Barcelona, Spain. ana.m.catafau@gsk.com
authors.forename: Ana M
authors.initials: AM
authors.lastname: Catafau
authors.forename: Graham E
authors.initials: GE
authors.lastname: Searle
authors.forename: Santiago
authors.initials: S
authors.lastname: Bullich
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: Raul
authors.initials: R
authors.lastname: Herance
authors.forename: Joaquim
authors.initials: J
authors.lastname: Radua
authors.forename: Magi
authors.initials: M
authors.lastname: Farre
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
mesh_terms: D000328:Adult; D000818:Animals; D001552:Benzazepines / Q000737:chemistry / Q000378:metabolism*; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D007650:Ketanserin / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists; D013194:Staining and Labeling / Q000379:methods; D055815:Young Adult
chemical_list: D001552:Benzazepines; D001572:Benzofurans; D002250:Carbon Radioisotopes; D017447:Receptors, Dopamine D1; D058830:Serotonin 5-HT2 Receptor Antagonists; C077123:NNC 112; D007650:Ketanserin