title: First human evidence of d-amphetamine induced displacement of a D2/3 agonist radioligand: A [11C]-(+)-PHNO positron emission tomography study.
abstract: Imaging the competition between D(2/3) radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D(2) receptor exists in a high (D(2)(high)) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D(2)(high) only. [(11)C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D(2/3) agonist radioligand for positron emission tomography (PET) imaging in humans. Since [(11)C]-(+)-PHNO is expected to bind preferentially to D(2)(high), it should be particularly vulnerable to competition with endogenous dopamine. Nine healthy subjects participated in two PET scans, one after administration of d-amphetamine and one after placebo. [(11)C]-(+)-PHNO PET test re-test variability was determined in 11 healthy subjects. Binding potentials (BPs) were calculated for caudate, putamen, ventral striatum, and globus pallidus. d-Amphetamine led to a significant decrease of [(11)C]-(+)-PHNO BPs in caudate (-13.2%), putamen (-20.8%), and ventral striatum (-24.9%), but not in globus pallidus (-6.5%). d-Amphetamine-induced displacement correlated with serum d-amphetamine levels in all regions but caudate. This is the first report on competition between endogenous dopamine and a D(2/3) agonist radioligand in humans. [(11)C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D(2/3) antagonist radioligands.
authors.affiliation: Positron Emission Tomography Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Matthäus
authors.initials: M
authors.lastname: Willeit
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ginovart
authors.forename: Ariel
authors.initials: A
authors.lastname: Graff
authors.forename: Pablo
authors.initials: P
authors.lastname: Rusjan
authors.forename: Irina
authors.initials: I
authors.lastname: Vitcu
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Philip
authors.initials: P
authors.lastname: Seeman
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D003913:Dextroamphetamine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000138:chemical synthesis; D005260:Female; D005917:Globus Pallidus / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D008297:Male; D010078:Oxazines / Q000138:chemical synthesis*; D049268:Positron-Emission Tomography; D011699:Putamen / Q000000981:diagnostic imaging / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D010078:Oxazines; C042631:naxagolide; D003913:Dextroamphetamine