title: Receptor binding and selectivity of three 11C-labelled dopamine receptor antagonists in the brain of rhesus monkeys studied with positron emission tomography.
abstract: The regional distribution of 3 11C-labelled dopamine receptor antagonists, N-methyl spiperone, raclopride and clozapine, in the brain of Rhesus monkeys was studied by positron emission tomography (PET). The measured radioactivities in the striatal area were similar for the 3 antagonists, although the highest selectivity as compared to cerebellum was found for 11C-raclopride 60 min after administration. The selectivity of the radiotracers for the serotonin and D2-dopamine receptors was evaluated after pretreatment of the monkeys with serotonin and dopamine receptor antagonists. 11C-N-methylspiperone and 11C-clozapine both bound to serotonin receptors in the frontal cortex and to D2-dopamine receptors in the striatal area. Raclopride was selectively bound to the D2-dopamine receptors. The radioactivities measured in the striatal area with cerebellum as reference were fitted to a 3-compartment model which made possible evaluation of receptor binding characteristics. The rate proportional to the association rate constant for the receptor, kon and number of receptors, Bmax, varied from 0.02-0.07 min-1 between the studied radiolabelled drugs, whereas the apparent dissociation rate was highest for clozapine. This means that clozapine had the lowest affinity for the receptors in the striatum, assuming that the Bmax values are identical. The observed difference in selective receptor binding and binding characteristics of the 3 tracers may have an influence both on the clinical efficacy and side effects of the studied dopamine receptor antagonists.
authors.affiliation: Department of Neurology, University Hosptial, University of Uppsala, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Hartvig
authors.forename: S A
authors.initials: SA
authors.lastname: Eckernäs
authors.forename: B
authors.initials: B
authors.lastname: Ekblom
authors.forename: L
authors.initials: L
authors.lastname: Lindström
authors.forename: H
authors.initials: H
authors.lastname: Lundqvist
authors.forename: S
authors.initials: S
authors.lastname: Axelsson
authors.forename: K J
authors.initials: KJ
authors.lastname: Fasth
authors.forename: P
authors.initials: P
authors.lastname: Gullberg
authors.forename: B
authors.initials: B
authors.lastname: Långström
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D003024:Clozapine / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D008253:Macaca mulatta; D020891:Raclopride; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D012457:Salicylamides / Q000378:metabolism / Q000494:pharmacology; D013134:Spiperone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D011954:Receptors, Dopamine; D012457:Salicylamides; D020891:Raclopride; D013134:Spiperone; C039167:3-N-methylspiperone; D003024:Clozapine