title: Acute effects of physostigmine and galantamine on the binding of [18F]fluoro-A-85380: a PET study in monkeys.
abstract: 2-[18F]fluoro-3-[2S-2-azetidinylmethoxy]pyridine ([18F]fluoro-A-85380) is an alpha4beta2 subtype selective nicotinic cholinergic agonist with potential suitability for studying changes in endogenous acetylcholine synaptic concentration. Physostigmine, a potent AChE inhibitor, and galantamine, an allosteric modulator of nAChRs, are widely used for the treatment of Alzheimer's disease. Before studying patients with this neurodegenerative disease, positron emission tomography (PET) studies in monkeys were performed to assess the impact of these two compounds on the radiotracer distribution volumes. Physostigmine was administered i.v. at two dosages: 150 microg/kg/h and 37.5 microg/kg/h for 160 min. Galantamine was administered i.v. at two dosages: 2 or 4 mg over 20 min. For PET data analysis, a model with one tissue (radioactivity of the parent compound in plasma and radioactivity in brain tissue) compartment was chosen because reliable parameter estimates could not be obtained with a more complex model. The higher dose of physostigmine produced a 40%, 23%, and 30% reduction of distribution volumes in the putamen, the temporal, and frontal cortices, respectively. The lower dose of physostigmine produced a reduction of 33%, 31%, and 24% in the same structures, respectively. Galantamine (4 mg or 2 mg) produced no significant change of distribution volumes in the basal ganglia, the temporal and frontal cortex. The effects of physostigmine, a more potent AChE inhibitor than galantamine, could be interpreted as a desensitization of nAChRs, due to a prolonged exposure to high synaptic concentration of acetylcholine or as a competition with acetylcholine.
authors.affiliation: Service Hospitalier Frédéric Joliot, Direction of Life Sciences, Department of Medical Research, French Atomic Agency, Orsay, France. valette@shfj.cea.fr
authors.forename: Héric
authors.initials: H
authors.lastname: Valette
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.forename: Christine
authors.initials: C
authors.lastname: Coulon
authors.forename: Michèle
authors.initials: M
authors.lastname: Ottaviani
authors.forename: André
authors.initials: A
authors.lastname: Syrota
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001384:Azetidines / Q000493:pharmacokinetics*; D001667:Binding, Competitive / Q000187:drug effects*; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005702:Galantamine / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D048531:Papio papio; D010830:Physostigmine / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D015203:Reproducibility of Results; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: C104288:A 85380; D001384:Azetidines; D002800:Cholinesterase Inhibitors; D005462:Fluorine Radioisotopes; D005702:Galantamine; D010830:Physostigmine