Amphetamine decreases α2C-adrenoceptor binding of [11C]ORM-13070: a PET study in the primate brain

Int J Neuropsychopharmacol. 2014 Dec 13;18(3):pyu081. doi: 10.1093/ijnp/pyu081.


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.

Keywords: PET; amphetamine; atipamezole; atomoxetine; monkey.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology
  • Adrenergic alpha-2 Receptor Antagonists / pharmacology
  • Amphetamine / pharmacology*
  • Animals
  • Atomoxetine Hydrochloride
  • Brain / drug effects*
  • Central Nervous System Stimulants / pharmacology*
  • Dioxanes / metabolism
  • Female
  • Humans
  • Imidazoles / pharmacology
  • Macaca fascicularis
  • Male
  • Piperazines / metabolism
  • Positron-Emission Tomography*
  • Propylamines / pharmacology
  • Protein Binding / drug effects
  • Radiopharmaceuticals / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • Time Factors


  • 1-(1-(2,3-dihydrobenzo(1,4)dioxin-2-yl)methyl)-4-(3-methoxymethylpyridin-2-yl)piperazine
  • Adrenergic Uptake Inhibitors
  • Adrenergic alpha-2 Receptor Antagonists
  • Central Nervous System Stimulants
  • Dioxanes
  • Imidazoles
  • Piperazines
  • Propylamines
  • Radiopharmaceuticals
  • Receptors, Adrenergic, alpha-2
  • atipamezole
  • Atomoxetine Hydrochloride
  • Amphetamine