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Acute effects of physostigmine and galantamine on the binding of [ 18 F]fluoro‐A‐85380: A PET study in monkeys
Author(s) -
Valette Héric,
Bottlaender Michel,
Dollé Frédéric,
Coulon Christine,
Ottaviani Michèle,
Syrota André
Publication year - 2005
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20145
Subject(s) - physostigmine , galantamine , chemistry , pharmacology , acetylcholinesterase inhibitor , cholinergic , acetylcholinesterase , acetylcholine , cholinesterase , nicotinic agonist , endocrinology , medicine , biochemistry , donepezil , receptor , dementia , disease , enzyme
Abstract 2‐[ 18 F]fluoro‐3‐[2(S)‐2‐azetidinylmethoxy]pyridine ([ 18 F]fluoro‐A‐85380) is an α4β2 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 μg/kg/h and 37.5 μg/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. Synapse 56:217–221, 2005. © 2005 Wiley‐Liss, Inc.