title: Regional brain distribution and binding of the muscarinic receptor agonist CI-979 studied by positron emission tomography in the monkey.
abstract: The regional brain distribution and selective binding of the cholinergic muscarinic receptor agonist CI-979 labelled with 11C was studied in rhesus monkeys by means of positron emission tomography. The selective binding was measured as displacement of [11C]CI-979-derived radioactivity following constant-rate infusion of CI-979 at doses of 0.5-10 micrograms/kg/h. An extensive and rapid distribution of [11C]CI-979 was observed to the basal ganglia and temporal occipital cortices, i.e., regions of the brain with a high density of muscarinic receptors. The radioactivity was dose-dependently decreased in cortical regions following infusions of unlabelled CI-979 (0.5-10 micrograms/kg/h), indicating selective receptor binding of [11C]CI-979 in these brain regions. The binding of [11C]CI-979 was unaltered or even higher in the striatum following unlabelled CI-979 infusion. The high densities of autoreceptors in the striatum may explain the inhibitory feedback mechanism on endogenous acetylcholine induced by the muscarinic receptor agonist. Since muscarinic receptor agonists release acetylcholine, the higher releasable pool of acetylcholine in the stratum will induce feedback inhibition of acetylcholine release and less competition between acetylcholine and CI-979 at the muscarinic receptors. This may explain the differences between cortex and striatum in [11C]CI-979 binding. The cerebral blood flow was not changed by the infusion of unlabelled CI-979, supporting the assumption that effects of CI-979 in brain may be due to the interaction with brain muscarinic receptors. Despite a relative rapid clearance of [11C]CI-979 radioactivity from binding in the brain characteristic of a receptor agonist, the radioligand might be useful in positron emission tomography studies to reveal changes in cholinergic receptors and functional activity in Alzheimer patients treated with muscarinic agonists.
authors.affiliation: Uppsala University Hospital, PET Centre, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Hartvig
authors.forename: R
authors.initials: R
authors.lastname: Torstenson
authors.forename: P
authors.initials: P
authors.lastname: Bjurling
authors.forename: K J
authors.initials: KJ
authors.lastname: Fasth
authors.forename: B
authors.initials: B
authors.lastname: Längström
authors.forename: A
authors.initials: A
authors.lastname: Nordberg
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000000981:diagnostic imaging / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004095:Dihydropyridines / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D007553:Isotope Labeling; D008253:Macaca mulatta; D018721:Muscarinic Agonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D010091:Oximes / Q000493:pharmacokinetics* / Q000494:pharmacology; D014055:Tomography, Emission-Computed
chemical_list: D004095:Dihydropyridines; D018721:Muscarinic Agonists; D010091:Oximes; C084978:milameline