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)

[18F]Fluoropropyl-TZTP (FP-TZTP) is a subtype-selective muscarinic cholinergic ligand with potential suitability for studying Alzheimer's disease. Positron emission tomography studies in isofluorane-anesthetized rhesus monkeys were performed to assess the in vivo behavior of this radiotracer. First, control studies (n = 11) were performed to characterize the tracer kinetics and to choose an appropriate model using a metabolite-corrected arterial input function. Second, preblocking studies (n = 4) with unlabeled FP-TZTP were used to measure nonspecific binding. Third, the sensitivity of [18F]FP-TZTP binding to changes in brain acetylcholine (ACh) was assessed by administering physostigmine, an acetylcholinesterase (AChE) inhibitor, by intravenous infusion (100 to 200 microg x kg(-1) x h(-1)) beginning 30 minutes before tracer injection (n = 7). Tracer uptake in the brain was rapid with K1 values of 0.4 to 0.6 mL x min(-1) x mL(-1) in gray matter. A model with one tissue compartment was chosen because reliable parameter estimates could not be obtained with a more complex model. Volume of distribution (V) values, determined from functional images created by pixel-by-pixel fitting, were very similar in cortical regions, basal ganglia, and thalamus, but significantly lower (P < 0.01) in the cerebellum, consistent with the distribution of M2 cholinergic receptors. Preblocking studies with unlabeled FP-TZTP reduced V by 60% to 70% in cortical and subcortical regions. Physostigmine produced a 35% reduction in cortical specific binding (P < 0.05), consistent with increased ACh competition. The reduction in basal ganglia (12%) was significantly smaller (P < 0.05), consistent with its markedly higher AChE activity. These studies indicate that [18F]FP-TZTP should be useful for the in vivo measurement of muscarinic receptors with positron emission tomography.
J Cereb Blood Flow Metab 1998 Oct
PMID:Muscarinic cholinergic receptor measurements with [18F]FP-TZTP: control and competition studies. 977 90

N-[11C]Methylpiperidin-4-yl propionate ([11C]PMP) is a substrate for hydrolysis by acetylcholinesterase (AChE). This work evaluates kinetic analysis alternatives for estimation of relative AChE activity using dynamic positron emission tomography (PET) studies of [11C]PMP. The PET studies were performed on three groups of subjects: (1) 12 normal volunteer subjects, aged 20 to 45 years, who received a single intravenous injection of 16 to 32 mCi of [11C]PMP; (2) six subjects, aged 21 to 44 years, who received two 16-mCi injections of [11C]PMP (baseline and visual stimulation, respectively); and (3) five subjects, aged 24 to 40 years, who received two 16-mCi injections separated by 200 minutes (baseline and after a 1-hour constant infusion of 1.5 mg of physostigmine, respectively). Dynamic acquisition consisted of a 17-frame sequence over 80 minutes. All analysis methods were based on a first-order kinetic model consisting of two tissue compartments with the parameter k3, representing PMP hydrolysis, being the index of AChE activity. Four different schemes were used to estimate k3: (1) an unconstrained non-linear least-squares fit estimating blood-brain barrier transport parameters, K1 and k2, in addition to the hydrolysis rate constant k3; (2) and (3), two methods of constraining the fit by fixing the volume of distribution of free tracer (DVfree); and (4), a direct estimation of k3 without use of an arterial input function based on the shape of the tissue time-activity curve alone. Results showed that k3 values from the unconstrained fitting and no input methods were estimated with similar accuracy, whereas the two methods using DVfree constraints yielded similar results. The authors conclude that the optimal analysis method for [11C]PMP differs as a function of AChE activity. All four methods gave precise measures of k3 in regions with low AChE activity (approximately 10% coefficient of variation in cortex), but surprisingly, with unconstrained methods yielding estimates with lower variability than constrained methods. In regions with moderate to high AChE activity, constrained methods were required to yield meaningful estimates and were superior to the unconstrained methods.
J Cereb Blood Flow Metab 1999 Oct
PMID:Kinetic modeling of N-[11C]methylpiperidin-4-yl propionate: alternatives for analysis of an irreversible positron emission tomography trace for measurement of acetylcholinesterase activity in human brain. 1053 40

Transcranial freeze lesions in neonatal rat pups produce microgyri and adjacent epileptogenic regions of neocortex that can be used to model human polymicrogyria. The hypothesis that the presence of microgyri is associated with abnormal cortical organization occurring within as well as adjacent to the microgyri was tested by creating microgyri within the face representation of somatosensory cortex. Microgyri were associated with a widespread disruption of the stereotypic whisker barrel field pattern delineated with cytochrome oxidase (CO) staining. CO-stained patches resembling barrel hollows were absent within the microgyrus, and were abnormally shaped and distributed outside of the microgyrus. Adjacent Nissl- or acetylcholinesterase-stained sections demonstrated that both cell clusters and thalamocortical afferents contributed to the abnormally organized paramicrogyral zone identified in CO-stained sections. Field potential recordings showed that this region of heavy CO staining corresponded to the epileptogenic zone adjacent to the microgyrus. Results support our hypothesis that the epileptogenic paramicrogyral zone develops an abnormal organization of cell clusters and thalamocortical projections that could contribute to epileptogenesis in the paramicrogyral zone.
Cereb Cortex
PMID:Experimental microgyri disrupt the barrel field pattern in rat somatosensory cortex. 1055 96

[11C]physostigmine, an acetylcholinesterase inhibitor, has been shown to be a promising positron emission tomography ligand to quantify the cerebral concentration of the enzyme in animals and humans in vivo. Here, a quantitative and noninvasive method to measure the regional acetylcholinesterase concentration in the brain is presented. The method is based on the observation that the ratio between regions rich in acetylcholinesterase and white matter, a region almost entirely deprived of this enzyme, was found to become approximately constant after 20 to 30 minutes, suggesting that at late time points the uptake mainly contains information about the distribution volume. Taking the white matter as the reference region, a simplified reference tissue model, with effectively one reversible tissue compartment and three parameters, was found to give a good description of the data in baboons. One of these parameters, the ratio between the total distribution volumes in the target and reference regions, showed a satisfactory correlation with the acetylcholinesterase concentration measured postmortem in two baboon brains. Eight healthy male subjects were also analyzed and the regional enzyme concentrations obtained again showed a good correlation with the known acetylcholinesterase concentrations measured in postmortem studies of human brain.
J Cereb Blood Flow Metab 2001 Feb
PMID:Quantitative measurement of cerebral acetylcholinesterase using. 1117 77

There is currently great interest in developing radiolabeled substrates for acetylcholinesterase and butyrylcholinesterase that would be useful in the in vivo imaging of patients with Alzheimer's disease. Using a simple in vitro spectrophotometric assay for determination of enzymatic cleavage rates, the structure-activity relationship for a short series of 1-methyl-4-piperidinyl esters was investigated. Relative enzymatic hydrolysis rates for the well-characterized 1-methyl-4-piperidinyl acetate, propionate, and i-butyrate esters were in agreement with literature values. The 4 and 5 carbon esters of 1-methyl-4-piperidinol were specific for butyrylcholinesterase and cleaved in the rank order n-valerate > n-butyrate >> 2-methylbutyrate, iso-valerate. These spectrophotometric results were also in agreement with in vitro hydrolysis rates in mouse blood and with in vivo regional retention of radioactivity in mouse brain of 11C-labeled analogs. Brain uptake and apparent enzymatic rate constants for 1-[11C]methyl-4-piperidinyl n-butyrate and n-valerate were calculated from in vivo measurements in M. nemistrina using positron emission tomography. Based on higher brain uptake of radioactivity and superior pharmacokinetics, 1-[11C]methyl-4-piperidinyl n-butyrate was identified as a new radiopharmaceutical for the in vivo measurement of butyrylcholinesterase activity.
J Cereb Blood Flow Metab 2001 Feb
PMID:Radiolabeled cholinesterase substrates: in vitro methods for determining structure-activity relationships and identification of a positron emission tomography radiopharmaceutical for in vivo measurement of butyrylcholinesterase activity. 1117 78

Although the inhibition of acetylcholinesterase remains the primary treatment of Alzheimer's disease, little is known of the results of increased acetylcholine levels on muscarinic receptor occupancy or function. Using N-(2-[18F]fluoroethyl)-4-piperidyl benzilate ([18F]FEPB), a moderate affinity (Ki = 1.7 nmol/L) nonsubtype-selective muscarinic receptor antagonist, the authors examined the sensitivity of equilibrium in vivo radioligand binding in rat brain with changes in endogenous acetylcholine levels produced by treatments with acetylcholinesterase inhibitors. Phenserine administration 30 minutes before resulted in a dose-dependent into muscarinic cholinergic receptors, reaching a maximum increase of 90% in the striatum at a dose of 5 mg/kg intraperitoneally. Constant infusion of physostigmine at a dosage of 250 microg/kg/min produced an identical increase in radioligand binding. This agonist-induced increase of in vivo mAChR radioligand binding offers a new method for monitoring of the efficacy of acetylcholinesterase inhibitors or other drugs to enhance acetylcholine actions at the muscarinic receptors.
J Cereb Blood Flow Metab 2001 Feb
PMID:Acetylcholinesterase inhibition increases in vivo N-(2-[18F]fluoroethyl)-4-piperidyl benzilate binding to muscarinic acetylcholine receptors. 1117 79

N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) is a radiotracer that has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET) using a standard compartment model analysis and a metabolite-corrected arterial input function. In the current study, the authors evaluated the applicability of a simple kinetic analysis without blood sampling, namely shape analysis. First, the authors used computer simulations to analyze factors that affect the precision and bias of shape analysis, then optimized the shape analysis procedure for [11C]MP4A. Before shape analysis execution, the later part of dynamic PET data except for the initial 3 minutes were smoothed by fitting to a bi-exponential function followed by linear interpolation of 8 data points between each of adjacent scan frames. Simulations showed that shape analysis yielded estimates of regional metabolic rates of [11C]MP4A by AChE (k3) with acceptable precision and bias in brain regions with low k3 values such as neocortex. Estimates in regions with higher k3 values became progressively more inaccurate. The authors then applied the method to [11C]MP4A PET data in 10 healthy subjects and 20 patients with Alzheimer's disease (AD). There was a highly significant linear correlation in regional k3 estimates between shape and compartment analyses (300 neocortical regions, [shape k3] = 0.93 x [NLS k3], r = 0.89, P < 0.001). Significant reductions in k3 estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral cortices in patients with AD as compared with controls were observed when using shape analysis (P < 0.013, two-tailed t-test), although these reductions (17% to 20%) were somewhat less than those obtained by compartment analysis (22% to 27%). The sensitivity of shape analysis for detecting neocortical regions with abnormally low k3 in the 20 patients with AD (92 out of 200 regions, 46%) also was somewhat less than compartment analysis (136 out of 200 regions, 68%). However, taking its simplicity and noninvasiveness into account, the authors conclude that quantitative measurement of neocortical AChE activity with shape analysis and [11C]MP4A PET is practical and useful for clinical diagnosis of AD.
J Cereb Blood Flow Metab 2001 Mar
PMID:Positron emission tomographic measurement of brain acetylcholinesterase activity using N-[(11)C]methylpiperidin-4-yl acetate without arterial blood sampling: methodology of shape analysis and its diagnostic power for Alzheimer's disease. 1129 84

The observations of the loss of cholinergic function in neocortex and hippocampus in Alzheimer's disease (AD) developed the hypothesis that replacement of cholinergic function may be of therapeutic benefit to AD patients. The different approaches proposed or tested included intervention with acetylcholine (ACh) precursors, stimulation of ACh release, use of muscarinic or nicotinic receptor agonists and acetylcholinesterase (AChE) or cholinesterase (ChE) inhibition. Inhibition of endogenous ACh degradation through ChE inhibitors and precursor loading were treatments more largely investigated in clinical trials. Of the numerous compounds in development for the treatment of AD, AChE and ChE inhibitors are the most clinically advanced, although clinical trials conducted to date did not always confirm a significant benefit of these drugs on all symptom domains of AD. The first attempts in the treatment of AD with cholinergic precursors did not confirm a clinical utility of this class of compounds in well controlled clinical trials. However, cholinergic precursors most largely used such as choline and phosphatidylcholine (lecithin) were probably not suitable for enhancing brain levels of ACh. Other phospholipids involved in choline biosynthetic pathways such as CDP-choline, choline alphoscerate and phosphatidylserine clearly enhanced ACh availability or release and provided a modest improvement of cognitive dysfunction in AD, these effects being more pronounced with choline alphoscerate. Although some positive results cannot be generalized due to the small numbers of patients studied, they probably would justify reconsideration of the most promising molecules in larger carefully controlled trials.
 ...
PMID:Treatment of cognitive dysfunction associated with Alzheimer's disease with cholinergic precursors. Ineffective treatments or inappropriate approaches? 1158 20

N -[(11)C]methylpiperidin-4-yl acetate ([(11)C]MP4A) is an acetylcholine analog. It has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET). [(11)C]MP4A is specifically hydrolyzed by AChE in the brain to a hydrophilic metabolite, which is irreversibly trapped locally in the brain. The authors propose a new method of kinetic analysis of brain AChE activity by PET without arterial blood sampling, that is, reference tissue-based linear least squares (RLS) analysis. In this method, cerebellum or striatum is used as a reference tissue. These regions, because of their high AChE activity, act as a biologic integrator of plasma input function during PET scanning, when regional metabolic rates of [(11)C]MP4A through AChE (k(3); an AChE index) are calculated by using Blomqvist's linear least squares analysis. Computer simulation studies showed that RLS analysis yielded k(3) with almost the same accuracy as the standard nonlinear least squares (NLS) analysis in brain regions with low (such as neocortex and hippocampus) and moderately high (thalamus) k(3) values. The authors then applied these methods to [(11) C]MP4A PET data in 12 healthy subjects and 26 patients with Alzheimer disease (AD) using the cerebellum as the reference region. There was a highly significant linear correlation in regional k(3) estimates between RLS and NLS analyses (456 cerebral regions, [RLS k(3) ] = 0.98 x [NLS k(3) ], r = 0.92, P < 0.001). Significant reductions were observed in k(3) estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral neocortices (P < 0.001, single-tailed t-test), and hippocampus (P = 0.012) in patients with AD as compared with controls when using RLS analysis. Mean reductions (19.6%) in these 6 regions by RLS were almost the same as those by NLS analysis (20.5%). The sensitivity of RLS analysis for detecting cortical regions with abnormally low k 3 in the 26 patients with AD (138 of 312 regions, 44%) was somewhat less than NLS analysis (52%), but was greater than shape analysis (33%), another method of [(11)C]MP4A kinetic analysis without blood sampling. The authors conclude that RLS analysis is practical and useful for routine analysis of clinical [(11)C]MP4A studies.
J Cereb Blood Flow Metab 2001 Nov
PMID:Kinetic analysis of [(11)C]MP4A using a high-radioactivity brain region that represents an integrated input function for measurement of cerebral acetylcholinesterase activity without arterial blood sampling. 1170 50

The parahippocampal gyrus, located at the medial temporal lobe, is a key structure in declarative memory processing. We have analyzed the general organization of the parahippocampal gyrus in the baboon, a nonhuman primate species relatively close to human. This region is rostrocaudally made up of the temporopolar, perirhinal, entorhinal (divided into seven subfields) and posterior parahippocampal (areas TH and TF) cortices. The basic analysis has been performed in three brains, serially sectioned and stained with thionin, myelin stain, acetylcholinesterase and parvalbumin, to determine cytoarchitectonic boundaries. Borders of all subfields were charted onto camera lucida drawings, and two-dimensional maps of the surface and topography of the parahippocampal gyrus were made. Finally, the limits of each parahippocampal area were then transposed on corresponding MR images (commonly used for in vivo PET or functional MRI activation studies) of two animals for precise identification. The general cytoarchitectonic features of the baboon parahippocampal gyrus are similar to macaques, but the size of temporopolar cortex and the laminar organization of perirhinal and posterior parahippocampal cortices resemble humans more than macaque species. In conclusion, the size and structure of the baboon parahippocampal cortex makes this species very appropriate for experimental studies on memory function.
Cereb Cortex 2004 Mar
PMID:The parahippocampal gyrus in the baboon: anatomical, cytoarchitectonic and magnetic resonance imaging (MRI) studies. 1475 64


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