title: Validation of [(11) C]ORM-13070 as a PET tracer for alpha2c -adrenoceptors in the human brain.
abstract: This study explored the use of the α2C -adrenoceptor PET tracer [(11) C]ORM-13070 to monitor α2C -AR occupancy in the human brain. The subtype-nonselective α2 -AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (Emax and EC50 ) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions. We assessed occupancy from the bound-to-free ratio measured during 5-30 min post injection. Based on extrapolation of one-site binding, the maximal extent of inhibition of striatal [(11) C]ORM-13070 uptake (Emax ) achievable by atipamezole was 78% (95% CI 69-87%) in the caudate nucleus and 65% (53-77%) in the putamen. The EC50 estimates of atipamezole (1.6 and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to α2C -ARs. These findings represent clear support for the use of [(11) C]ORM-13070 for monitoring drug occupancy of α2C -ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10-16% average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine, and the cold pressor test; P < 0.05 for all), but insulin-induced hypoglycemia did not affect tracer uptake. The tracer is suitable for studying central nervous system receptor occupancy by α2C -AR ligands in human subjects. [(11) C]ORM-13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies.
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland; Clinical Research Services Turku CRST, Turku, Finland; Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Lehto
authors.forename: Mika M
authors.initials: MM
authors.lastname: Hirvonen
authors.forename: Jarkko
authors.initials: J
authors.lastname: Johansson
authors.forename: Jukka
authors.initials: J
authors.lastname: Kemppainen
authors.forename: Pauliina
authors.initials: P
authors.lastname: Luoto
authors.forename: Tarja
authors.initials: T
authors.lastname: Naukkarinen
authors.forename: Vesa
authors.initials: V
authors.lastname: Oikonen
authors.forename: Eveliina
authors.initials: E
authors.lastname: Arponen
authors.forename: Juha
authors.initials: J
authors.lastname: Rouru
authors.forename: Jukka
authors.initials: J
authors.lastname: Sallinen
authors.forename: Harry
authors.initials: H
authors.lastname: Scheinin
authors.forename: Lauri
authors.initials: L
authors.lastname: Vuorilehto
authors.forename: Sjoerd J
authors.initials: SJ
authors.lastname: Finnema
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Juha O
authors.initials: JO
authors.lastname: Rinne
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000493:pharmacokinetics; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging*; D004146:Dioxanes / Q000493:pharmacokinetics*; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics; D008297:Male; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C000598340:1-(1-(2,3-dihydrobenzo(1,4)dioxin-2-yl)methyl)-4-(3-methoxymethylpyridin-2-yl)piperazine; D058669:Adrenergic alpha-2 Receptor Antagonists; D004146:Dioxanes; D007093:Imidazoles; D010879:Piperazines; D019275:Radiopharmaceuticals; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole
keywords: PET; alpha2-adrenoceptors; atipamezole; atomoxetine; ketamine; noradrenaline