title: In vivo vulnerability to competition by endogenous dopamine: comparison of the D2 receptor agonist radiotracer (-)-N-[11C]propyl-norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride.
abstract: (-)-N-Propyl-norapomorphine (NPA) is a full dopamine (DA) D2 receptor agonist and [11C]NPA is a suitable radiotracer to image D2 receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic DA was assessed with PET in baboons and compared to that of the reference D2 receptor antagonist radiotracer [11C]raclopride. Three male baboons were studied with [11C]raclopride and [11C]NPA under baseline conditions and following administration of the potent DA releaser amphetamine (0.3, 0.5, and 1.0 mg kg(-1) i.v.). Kinetic modeling with an arterial input function was used to derive the striatal specific-to-nonspecific equilibrium partition coefficient (V3"). [11C]Raclopride V3" was reduced by 24 +/- 10%, 32 +/- 6%, and 44 +/- 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg(-1), respectively. [11C]NPA V3" was reduced by 32 +/- 2%, 45 +/- 3%, and 53 +/- 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg(-1), respectively. Thus, endogenous DA was more effective at competing with [11C]NPA binding compared to [11C]raclopride binding, a finding consistent with the pharmacology of these tracers (agonist vs. antagonist). These results also suggest that 71% of D2 receptors are configured in a state of high affinity for agonists in vivo. In conclusion, [11C]NPA might provide a superior radiotracer to probe presynaptic DA function with PET in health and disease.
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY 10032, USA. rn2012@columbia.edu
authors.forename: Rajesh
authors.initials: R
authors.lastname: Narendran
authors.forename: Dah-Ren
authors.initials: DR
authors.lastname: Hwang
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.forename: Peter S
authors.initials: PS
authors.lastname: Talbot
authors.forename: David
authors.initials: D
authors.lastname: Erritzoe
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Cooper
authors.forename: Diana
authors.initials: D
authors.lastname: Martinez
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kegeles
authors.forename: Anissa
authors.initials: A
authors.lastname: Abi-Dargham
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
mesh_terms: D000465:Algorithms; D000661:Amphetamine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives*; D001667:Binding, Competitive / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics; D018765:Dopamine Uptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D010215:Papio; D020891:Raclopride / Q000138:chemical synthesis / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D014055:Tomography, Emission-Computed
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D020891:Raclopride; C009074:N-n-propylnorapomorphine; D000661:Amphetamine; D001058:Apomorphine; D004298:Dopamine