title: Amphetamine decreases α2C-adrenoceptor binding of [11C]ORM-13070: a PET study in the primate brain.
abstract: BACKGROUND
  The neurotransmitter norepinephrine has been implicated in psychiatric and neurodegenerative disorders. Examination of synaptic norepinephrine concentrations in the living brain may be possible with positron emission tomography (PET), but has been hampered by the lack of suitable radioligands.
  
  
  METHODS
  We explored the use of the novel α2C-adrenoceptor antagonist PET tracer [(11)C]ORM-13070 for measurement of amphetamine-induced changes in synaptic norepinephrine. The effect of amphetamine on [(11)C]ORM-13070 binding was evaluated ex vivo in rat brain sections and in vivo with PET imaging in monkeys.
  
  
  RESULTS
  Microdialysis experiments confirmed amphetamine-induced elevations in rat striatal norepinephrine and dopamine concentrations. Regional [(11)C]ORM-13070 receptor binding was high in the striatum and low in the cerebellum. After injection of [(11)C]ORM-13070 in rats, mean striatal specific binding ratios, determined using cerebellum as a reference region, were 1.4±0.3 after vehicle pretreatment and 1.2±0.2 after amphetamine administration (0.3mg/kg, subcutaneous). Injection of [(11)C]ORM-13070 in non-human primates resulted in mean striatal binding potential (BP ND) estimates of 0.65±0.12 at baseline. Intravenous administration of amphetamine (0.5 and 1.0mg/kg, i.v.) reduced BP ND values by 31-50%. Amphetamine (0.3mg/kg, subcutaneous) increased extracellular norepinephrine (by 400%) and dopamine (by 270%) in rat striata.
  
  
  CONCLUSIONS
  Together, these results indicate that [(11)C]ORM-13070 may be a useful tool for evaluation of synaptic norepinephrine concentrations in vivo. Future studies are required to further understand a potential contribution of dopamine to the amphetamine-induced effect.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde) sjoerd.finnema@ki.se.
authors.forename: Sjoerd J
authors.initials: SJ
authors.lastname: Finnema
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Zoë A
authors.initials: ZA
authors.lastname: Hughes
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Merja
authors.initials: M
authors.lastname: Haaparanta-Solin
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Vladimir
authors.initials: V
authors.lastname: Stepanov
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Ryuji
authors.initials: R
authors.lastname: Nakao
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Katarina
authors.initials: K
authors.lastname: Varnäs
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Eveliina
authors.initials: E
authors.lastname: Arponen
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Päivi
authors.initials: P
authors.lastname: Marjamäki
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Katariina
authors.initials: K
authors.lastname: Pohjanoksa
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Lauri
authors.initials: L
authors.lastname: Vuorilehto
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Phebian A
authors.initials: PA
authors.lastname: Babalola
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Olof
authors.initials: O
authors.lastname: Solin
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Sarah
authors.initials: S
authors.lastname: Grimwood
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Jukka
authors.initials: J
authors.lastname: Sallinen
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden (Drs Finnema, Stepanov, Nakao, Varnäs, Varrone, Farde, and Halldin); Pfizer, Neuroscience Research Unit, Cambridge, MA (Drs Hughes, Babalola, and Grimwood); University of Turku, Turku PET Centre, Turku, Finland (Drs Haaparanta-Solin, Arponen, Marjamäki, and Solin); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, and Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland (Drs Pohjanoksa, Vuorilehto, and Scheinin); Orion Corporation, Orion Pharma, Research and Development, Turku, Finland (Dr Sallinen); AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden (Dr Farde).
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001921:Brain / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004146:Dioxanes / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D010879:Piperazines / Q000378:metabolism; D049268:Positron-Emission Tomography; D011437:Propylamines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D019275:Radiopharmaceuticals / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013997:Time Factors
chemical_list: C000598340:1-(1-(2,3-dihydrobenzo(1,4)dioxin-2-yl)methyl)-4-(3-methoxymethylpyridin-2-yl)piperazine; D018759:Adrenergic Uptake Inhibitors; D058669:Adrenergic alpha-2 Receptor Antagonists; D000697:Central Nervous System Stimulants; D004146:Dioxanes; D007093:Imidazoles; D010879:Piperazines; D011437:Propylamines; D019275:Radiopharmaceuticals; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D000069445:Atomoxetine Hydrochloride; D000661:Amphetamine
keywords: PET; amphetamine; atipamezole; atomoxetine; monkey