Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We developed PET ligands (+)N-[(11)C]ethyl-3-piperidyl benzilate ([(11)C](+)3-EPB) and (+)N-[(11)C]propyl-3-piperidyl benzilate ([(11)C](+)3-PPB) for cerebral muscarinic cholinergic receptors. The distribution and kinetics of the novel ligands were evaluated for comparison with the previously reported ligand (+)N-[(11)C]methyl-3-piperidyl benzilate ([(11)C](+)3-MPB) in the monkey brain (Macaca mulatta) in the conscious state using high-resolution positron emission tomography (PET). At 60-91 min postinjection, regional distribution patterns of these three ligands were almost identical, and were consistent with the muscarinic receptor density in the brain as previously reported in vitro. However, the time-activity curves of [(11)C](+)3-EPB and [(11)C](+)3-PPB showed earlier peak times of radioactivity and a faster clearance rate than [(11)C](+)3-MPB in cortical regions rich in the receptors. Kinetic analysis using the three-compartment model with time-activity curves of radioactivity in metabolite-corrected arterial plasma as input functions revealed that labeling with longer [(11)C]alkyl chain length induced lower binding potential (BP = k(3)/k(4)), consistent with the rank order of affinity of these ligands obtained by an in vitro assay using rat brain slices and [(3)H]QNB. The cholinesterase inhibitor Aricept administered at doses of 50 and 250 microg/kg increased acetylcholine level in extracellular fluid of the frontal cortex and the binding of [(11)C](+)3-PPB with the lowest affinity to the receptors was displaced by the endogenous acetylcholine induced by cholinesterase inhibition, while [(11)C](+)3-MPB with the highest affinity was not significantly affected. Taken together, these observations indicate that the increase in [(11)C]alkyl chain length could alter the kinetic properties of conventional receptor ligands for PET by reducing the affinity to receptors, which might make it possible to assess the interaction between endogenous neurotransmitters and ligand-receptor binding in vivo as measured by PET.
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PMID:Evaluation of PET ligands (+)N-[(11)C]ethyl-3-piperidyl benzilate and (+)N-[(11)C]propyl-3-piperidyl benzilate for muscarinic cholinergic receptors: a PET study with microdialysis in comparison with (+)N-[(11)C]methyl-3-piperidyl benzilate in the conscious monkey brain. 1130 53

This study demonstrated the effects of acute acetylcholinesterase (AChE) inhibition by donepezil (Aricept) on the cerebral cholinergic neuronal system in the brains of young (5.2 +/- 1.1 years old) and aged (20.3 +/- 2.6 years old) monkeys (Macaca mulatta) in the conscious state. Donepezil at doses of 50 and 250 microg/kg suppressed AChE activity, analyzed by metabolic rate (k(3)) of N-[(11)C]methyl-4-piperidyl acetate ([(11)C]MP4A), in all cortical regions in a dose-dependent manner in both age groups. However, the suppression degree was more marked in young than in aged monkeys. AChE inhibition by donepezil resulted in a dose-dependent increase in acetylcholine levels in the prefrontal cortex of young animals as measured by microdialysis. Binding of (+)N-[(11)C]propyl-3-piperidyl benzilate ([(11)C](+)3-PPB) to cortical muscarinic receptors was reduced by donepezil, probably in a competitive inhibition manner. Aged monkeys showed less reduction of [(11)C](+)3-PPB binding than young animals. As evaluated by an oculomotor delayed response task, aged monkeys showed impaired working memory performance compared to young monkeys, and the impaired performance was partly improved by the administration of donepezil, due to the facilitation of the cholinergic neuronal system by AChE inhibition. These results demonstrate that the PET imaging technique with specific labeled compounds in combination with microdialysis and a behavioral cognition task could be a useful method to clarify the mechanism of drugs in the living brains of experimental animals.
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PMID:Effects of acute acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function: Functional imaging of the conscious monkey brain using animal PET in combination with microdialysis. 1475 27

The present review described the effects of acetylcholinesterase (AChE) inhibition on the cerebral cholinergic neuronal system in the conscious monkey brains with PET. Somatosensory stimulation induced a regional cerebral blood flow (rCBF) response, revealed with [(15)O]H(2)O, in the contralateral somatosensory cortex. Scopolamine resulted in an abolished rCBF response to stimulation, and this abolished rCBF response was recovered by physostigmine, donepezil, and tacrine. Donepezil suppressed AChE activity, analyzed by [(11)C]MP4A, in all cortical regions in a dose-dependent manner. AChE inhibition by donepezil resulted in a dose-dependent increase in acetylcholine levels in the prefrontal cortex as measured by microdialysis. Binding of [(11)C](+)3-PPB to cortical muscarinic receptors was reduced by donepezil, probably in a competitive inhibition manner. Aged monkeys showed less reduction of [(11)C](+)3-PPB binding than young animals. As evaluated by an oculomotor delayed response task, aged monkeys showed impaired working memory performance compared to young monkeys, and the impaired performance was partly improved by the administration of donepezil, due to the facilitation of the cholinergic neuronal system by AChE inhibition by donepezil. These results demonstrated that PET imaging with specifically labeled compounds in combination with microdialysis and a behavioral cognition task could be a useful tool for pre-clinical evaluation of novel drugs.
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PMID:[Pre-clinical evaluation of effects of acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function: PET study in conscious monkeys]. 1533 88