title: Development of a simultaneous PET/microdialysis method to identify the optimal dose of 11C-raclopride for small animal imaging.
abstract: In the field of small animal positron emission tomography (PET), the assumptions underlying human and primate kinetic models may not be sustained in rodents. That is, the threshold dose at which a pharmacologic response occurs may be lower in small animals. In order to define this relationship, we combined microPET imaging using 11C-raclopride with microdialysis measures of extracellular fluid (ECF) dopamine (DA). In addition, we performed a series of studies in which a known mass of raclopride was microinfused into one striatum prior to a high specific activity (SA) systemic injection of 11C-raclopride. This single-injection approach provided a high and low SA region of radiotracer binding in the same animal during the same scanning session. Our data demonstrate that the binding potential (BP) declines above 3.5 pmol/ml (0.35 microg), with an ED50 of 8.55+/-5.62 pmol/ml. These data also provide evidence that BP may be compromised by masses of raclopride below 2.0 pmol/ml (0.326 microg). Increases in ECF DA were produced by mass doses of raclopride over 3.9 pmol/ml (0.329 microg) with an ED50 of 8.53+/-2.48 pmol/ml. Taken together, it appears that an optimal range of raclopride mass exists between 2.0 and 3.5 pmol/ml, around which the measured BP can be compromised by system sensitivity, endogenous DA, or excessive competition with unlabeled compound.
authors.affiliation: Department of Neurobiology and Behavior, State University of New York at Stony Brook, NY 11794-5230, USA. wynne@bnl.gov
authors.forename: Wynne K
authors.initials: WK
authors.lastname: Schiffer
authors.forename: David L
authors.initials: DL
authors.lastname: Alexoff
authors.forename: Colleen
authors.initials: C
authors.lastname: Shea
authors.forename: Jean
authors.initials: J
authors.lastname: Logan
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Dewey
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging* / Q000378:metabolism; D001931:Brain Mapping; D002247:Carbon Isotopes / Q000097:blood / Q000493:pharmacokinetics*; D018492:Dopamine Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality; D008297:Male; D017551:Microdialysis / Q000379:methods*; D049268:Positron-Emission Tomography / Q000379:methods*; D020891:Raclopride / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D002247:Carbon Isotopes; D018492:Dopamine Antagonists; D020891:Raclopride