title: Effect of amphetamine on dopamine D2 receptor binding in nonhuman primate brain: a comparison of the agonist radioligand [11C]MNPA and antagonist [11C]raclopride.
abstract: PET measurements of stimulant-induced dopamine (DA) release are typically performed with antagonist radioligands that bind to both the high- and low-affinity state of the receptor. In contrast, an agonist radioligand binds preferentially to the high-affinity state and is expected to have greater sensitivity to DA, which is the endogenous agonist. [(11)C]MNPA, (R)-2-CH(3)O-N-n-propylnorapomorphine (MNPA), is a D(2) agonist radioligand with subnanomolar affinity to the D(2) receptor. The aim of the present study is to assess and compare the sensitivity of the agonist radioligand [(11)C]MNPA and antagonist radioligand [(11)C]raclopride to synaptic DA levels. Four cynomolgus monkeys were examined with [(11)C]MNPA and [(11)C]raclopride (16 PET measurements with each tracer) at baseline and after pretreatment with various doses of amphetamine. The effect of amphetamine was calculated by the change in binding potential (BP) analyzed with the multilinear reference tissue model (MRTM2). Amphetamine caused a reduction in [(11)C]MNPA BP of 4% at 0.1, 23% at 0.2, 25% at 0.5, and 46% at 1.0 mg/kg. [(11)C]Raclopride BP was reduced to a lesser extent by 2% at 0.1, 16% at 0.2, 15% at 0.5, and 23% at 1.0 mg/kg. The data were used to estimate the in vivo percentage of high-affinity state receptors to be approximately 60%. These results demonstrate that [(11)C]MNPA is more sensitive than [(11)C]raclopride to displacement by endogenous DA, and that it may provide additional information about the functional state of the D(2) receptor in illnesses such as schizophrenia and Parkinson's disease.
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska Hospital, S-17176 Stockholm, Sweden. Nick.Seneca@cns.ki.se
authors.forename: Nicholas
authors.initials: N
authors.lastname: Seneca
authors.forename: Sjoerd J
authors.initials: SJ
authors.lastname: Finnema
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.forename: Håkan V
authors.initials: HV
authors.lastname: Wikström
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry; D018491:Dopamine Agonists / Q000493:pharmacokinetics; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008252:Macaca fascicularis; D009288:Naproxen / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D020891:Raclopride / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D020891:Raclopride; D009288:Naproxen; D000661:Amphetamine