title: Detecting a dexmedetomidine-evoked reduction of noradrenaline release in the human brain with the alpha2C-adrenoceptor PET ligand [11C]ORM-13070.
abstract: PET imaging can for some neurotransmitters be used to measure synaptic neurotransmitter concentrations. The objective of this study was to test whether the receptor binding of the α2C -AR antagonist PET tracer [(11)C]ORM-13070 would increase in response to reductions in synaptic noradrenaline, evoked by dexmedetomidine as a sympatholytic drug challenge. Six subjects underwent a control PET scan and two dexmedetomidine PET scans. Dexmedetomidine was infused with target plasma concentrations of 0.6 and 0.2 ng/ml. Tracer binding was measured by voxel-based analysis of bound per free (B/F) images. ROI-based analysis was performed in the dorsal striatum and in the thalamus. Vital signs and drug concentrations in plasma were measured and the sedative effect was estimated with the visual analog scale. In the voxel-based analysis, dexmedetomidine administration was associated with a tendency to increased B/F tracer in the right thalamus (mean, +17%, P = 0.14, and +19%, P = 0.05, with the low and high dose, respectively). Tracer binding in the dorsal striatum was unaffected by dexmedetomidine. A cluster with significantly increased B/F tracer (+42%, P = 0.01) was seen in the right superior temporal gyrus with low-dose dexmedetomidine, but not after the high dose. Brain uptake of [(11)C]ORM-13070 has previously been shown to be reduced in conditions of increased synaptic noradrenaline concentrations. In this study, tracer binding in the thalamus tended to increase in accordance with reduced activity of noradrenergic projections from the locus coeruleus, but statistical significance was not reached.
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.affiliation: Turku PET Centre, University of Turku, Turku University Hospital, Turku, Finland.
authors.forename: Annalotta
authors.initials: A
authors.lastname: Scheinin
authors.affiliation: Turku PET Centre, University of Turku, Turku University Hospital, Turku, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Johansson
authors.affiliation: Turku PET Centre, University of Turku, Turku University Hospital, Turku, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Marjamäki
authors.affiliation: Turku PET Centre, University of Turku, Turku University Hospital, Turku, Finland.
authors.forename: Eveliina
authors.initials: E
authors.lastname: Arponen
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.|Turku PET Centre, University of Turku, Turku University Hospital, Turku, Finland.
authors.forename: Harry
authors.initials: H
authors.lastname: Scheinin
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: Mika
authors.initials: M
authors.lastname: Scheinin
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D020927:Dexmedetomidine / Q000009:adverse effects / Q000494:pharmacology*; D004146:Dioxanes / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: C000598340:1-(1-(2,3-dihydrobenzo(1,4)dioxin-2-yl)methyl)-4-(3-methoxymethylpyridin-2-yl)piperazine; D018712:Analgesics, Non-Narcotic; D004146:Dioxanes; D010879:Piperazines; D019275:Radiopharmaceuticals; D020927:Dexmedetomidine; D009638:Norepinephrine
keywords: PET; alpha2C-adrenoceptor; carbon-11; dexmedetomidine; noradrenaline