title: Quantitative validation of an intracerebral beta-sensitive microprobe system to determine in vivo drug-induced receptor occupancy using [11C]raclopride in rats.
abstract: In this study, we evaluated the potential of using a new beta-sensitive microprobe system for in vivo quantification of [11C]raclopride binding and for in vivo determination of drug-induced receptor occupancy in the rat striatum. To validate this system, an ex vivo tissue dissection method was used to corroborate in vivo beta-microprobe measurements. Our data showed that the beta-microprobe-derived [11C]raclopride binding kinetics in striatum could be quantified using a tissue compartmental model with a cerebellar reference region. Haloperidol (0.001-0.1 mg/kg; i.v.) induced a dose-dependent decrease in [11C]raclopride binding in striatum as measured using the beta-microprobe with an ED50 value of 0.013 mg/kg. Highly significant relationships (P < 0.0001) were observed, within the same animals, between in vivo and ex vivo measures of haloperidol-induced D2-receptor occupancy (r = 0.98) as well as between in vivo and ex vivo measures of [11C]raclopride binding potentials (r = 0.99). Results from pretreatment and displacement studies with unlabeled raclopride and amphetamine conformed to the effect of these drugs as observed in humans using [11C]raclopride and PET and allowed estimation of the in vivo k(off) value of raclopride to 0.025 +/- 0.004 min(-1). However, allowing the system to stabilize before measurements and shielding the photomultiplier tubes were critical for obtaining these consistent results. This study demonstrates that the beta-microprobe provides reliable measurements of [11C]raclopride binding kinetics in rodents, allows for quantitative in vivo measurements of antipsychotic drug action in brain, and represents a valid and cost-effective alternative to positron emission tomography imaging in small animals.
authors.affiliation: PET Centre, Centre for Addiction and Mental Health and University of Toronto, Toronto, Ontario M5T 1R8, Canada. nathalie.ginovart@camhpet.ca
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ginovart
authors.forename: Wenshan
authors.initials: W
authors.lastname: Sun
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D000818:Animals; D001610:Beta Particles; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D011485:Protein Binding / Q000502:physiology; D020891:Raclopride / Q000378:metabolism*; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D012588:Scintillation Counting / Q000379:methods*
chemical_list: D020891:Raclopride