title: In vivo characterization of the pharmacokinetics and pharmacological properties of [11C]-(+)-PHNO in rats using an intracerebral beta-sensitive system.
abstract: This study reports on the binding kinetics and pharmacological characterization of [11C]-(+)-PHNO ((+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol), a promising agonist radiotracer for in vivo evaluation of the D2-receptor. Its in vivo kinetics were monitored in rat striatum and cerebellum using a beta-sensitive Microprobe system. Control studies showed that [11C]-(+)-PHNO binding was reversible and reached a peak time equilibrium of specific binding in striatum 30 min after radiotracer injection. The binding potential (BP) calculated by the simplified reference tissue model was 3-fold higher than that measured with [11C]-(-)-NPA (2.14 +/- 0.50 vs. 0.66 +/- 0.01, respectively). In contrast, the methyl analog of (+)-PHNO, [11C]-(+)-MHNO, which displayed promising D2-agonist properties in vitro, showed no specific binding in the striatum in vivo. [11C]-(+)-PHNO binding was totally blocked by raclopride (1 mg/kg; i.v.) and 97% displaced by NPA (2 mg/kg; i.v.) suggesting that [11C]-(+)-PHNO was specific for the high affinity states of D2/D3-receptors. However, (+)-PHNO (1 mg/kg; i.v.) totally blocked and displaced [11C]-raclopride binding in striatum. Thus, (+)-PHNO at high concentrations might be able to bind to the low affinity states of D2/D3-receptors. After an amphetamine pretreatment (2 mg/kg; i.v.), a 69% decrease in BP value (P < 0.05) was observed for [11C]-(+)-PHNO indicating that its binding was highly sensitive to variations of endogenous DA. These results substantiate the use of [11C]-(+)-PHNO as an agonist radiotracer for D2-imaging. The sensitivity of its binding to competition with endogenous DA suggests an association with the subset of high affinity state D2-receptors.
authors.affiliation: The Vivian Rakoff Positron Emission Tomography Unit, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. laurent.galineau@camhpet.ca
authors.forename: Laurent
authors.initials: L
authors.lastname: Galineau
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Armando
authors.initials: A
authors.lastname: Garcia
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ginovart
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002250:Carbon Radioisotopes; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D008297:Male; D015394:Molecular Structure; D010078:Oxazines / Q000378:metabolism* / Q000493:pharmacokinetics*; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000032:analysis / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010078:Oxazines; D017448:Receptors, Dopamine D2; C042631:naxagolide; D020891:Raclopride; D000661:Amphetamine; D004298:Dopamine