Irie T

References (45)

Title : Voxel-Based Acetylcholinesterase PET Study in Early and Late Onset Alzheimer's Disease - Hirano_2018_J.Alzheimers.Dis_62_1539
Author(s) : Hirano S , Shinotoh H , Shimada H , Ota T , Sato K , Tanaka N , Zhang MR , Higuchi M , Fukushi K , Irie T , Kuwabara S , Suhara T
Ref : J Alzheimers Dis , 62 :1539 , 2018
Abstract : BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset. OBJECTIVE: The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N-[11C]methylpiperidinyl-4-acetate ([11C]MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age. METHODS: 22 early onset AD (EOAD) with age at onset under 65, the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [11C]MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p-value <0.05 on cluster-level and cluster extent over 30 voxels. RESULTS: Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann's area 22, Zmax = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart. CONCLUSION: Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD.
ESTHER : Hirano_2018_J.Alzheimers.Dis_62_1539
PubMedSearch : Hirano_2018_J.Alzheimers.Dis_62_1539
PubMedID: 29562505

Title : PET measurement of brain acetylcholinesterase activities in cortex and subcortical areas -
Author(s) : Shimada H , Hirano S , Shinotoh H , Irie T , Suhara T
Ref : Int J Geriatr Psychiatry , 31 :952 , 2016
PubMedID: 26555765

Title : Dementia with Lewy bodies can be well-differentiated from Alzheimer's disease by measurement of brain acetylcholinesterase activity-a [(11) C]MP4A PET study - Shimada_2015_Int.J.Geriatr.Psychiatry_30_1105
Author(s) : Shimada H , Hirano S , Sinotoh H , Ota T , Tanaka N , Sato K , Yamada M , Fukushi K , Irie T , Zhang MR , Higuchi M , Kuwabara S , Suhara T
Ref : Int J Geriatr Psychiatry , 30 :1105 , 2015
Abstract : OBJECTIVE: To investigate the diagnostic performance of brain acetylcholinesterase (AChE) activity measurement using N-[(11) C]-methyl-4-piperidyl acetate (MP4A) and PET in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).
METHODS: Participants were 14 DLB patients, 25 AD patients and 18 age-matched healthy controls (HC). All subjects underwent PET scans and MP4A to measure regional brain AChE activity. We performed anatomical standardization of each brain image, and k3 values, an index of AChE activity, in each voxel were estimated by nonlinear least squares analysis. Volumes of interest (VOIs) were identified on parametric k3 images in frontal, temporal, parietal and occipital cortices, and in anterior and posterior cingulate gyri (ACG and PCG). In each VOI, the differential diagnostic performance between AD and DLB of k3 values was assessed by area under the curve (AUC) of the receiver-operating characteristic. Voxel-based statistical analyses were also performed.
RESULTS: Mean cortical AChE activities in AD patients (-8.2% compared with normal mean) and DLB patients (-27.8%) were lower than HCs (p < 0.05, p < 0.001, respectively). There was a significant difference in mean cortical AChE activities between AD and DLB patients (p < 0.001). All regional brain AChE activities of defined VOIs except ACG were able to well discriminate DLB from AD, and notably performance was the most significant in PCG (AUC = 0.989, 95% CI: 0.965-1.000).
CONCLUSIONS: Brain cholinergic deficit is consistently prominent in DLB compared with AD. PET measurement of brain AChE activity may be useful for the differential diagnosis between DLB and AD. Copyright (c) 2015 John Wiley & Sons, Ltd.
ESTHER : Shimada_2015_Int.J.Geriatr.Psychiatry_30_1105
PubMedSearch : Shimada_2015_Int.J.Geriatr.Psychiatry_30_1105
PubMedID: 26280153

Title : PET probes for imaging brain acetylcholinesterase - Kikuchi_2013_J.Labelled.Comp.Radiopharm_56_172
Author(s) : Kikuchi T , Okamura T , Zhang MR , Irie T
Ref : J Labelled Comp Radiopharm , 56 :172 , 2013
Abstract : Imaging acetylcholinesterase (AChE) is valuable not only for diagnosing and understanding dementia but also for monitoring the effects of cholinesterase inhibitors used as antidementia drugs and for determining the appropriate clinical dosage of newly developed cholinesterase inhibitors. The distribution of AChE in the living brain can be imaged with two different types of radioprobes, including substrate-type and ligand-type probes. The substrate-type positron emission tomography (PET) probes, N-[(11) C]methylpiperidin-4-yl acetate ([(11) C]MP4A), and its propionate, [(11) C]MP4P, have been widely used in clinical studies of dementia, including Alzheimer's disease. [(11) C]MP4A and [(11) C]MP4P have been used to demonstrate a reduction in AChE activity in the brains of dementia patients, as well as the bioavailability of AChE inhibitors, leading to the subsequent development of the widely available (18) F-labeled derivatives of MP4A. In addition, several radiolabeled cholinesterase inhibitors have been developed as PET probes for AChE mapping in the brain. Herein, we have reviewed the development of PET probes for the imaging of AChE in the brain and described the principles of measuring AChE activity in the brain using PET with substrate-type radioprobes. A discussion of the reagents developed from substrate-type PET probes for the specific measurement of AChE activity in vitro has also been provided.
ESTHER : Kikuchi_2013_J.Labelled.Comp.Radiopharm_56_172
PubMedSearch : Kikuchi_2013_J.Labelled.Comp.Radiopharm_56_172
PubMedID: 24285323

Title : A method to predict the ratio of the tracer conversion rate to the tracer back-diffusion rate of an irreversible-type radiotracer in humans by preclinical evaluations - Ohya_2012_Nucl.Med.Commun_33_1019
Author(s) : Ohya T , Zhang MR , Fukumura T , Fukushi K , Kikuchi T , Irie T
Ref : Nucl Med Commun , 33 :1019 , 2012
Abstract : OBJECTIVE: The aim of this study was to develop a method to predict a tracer's alpha-value in the human brain on the basis of animal data. The alpha-value is the ratio of the conversion rate and the back-diffusion rate (k3/k2) and is one of the critical kinetic features of the detection sensitivity of target molecule activity, such as enzyme activity, in the measurement of PET and single-photon emission computed tomography using an irreversible-type radiotracer. METHOD: The alpha-value in the rat brain was estimated by a simultaneous assay of the tracer uptake and the target biochemical activity using N-[C]-methylpiperidin-4-yl acetate ([C]MP4A) and N-[C]-methylpiperidin-4-yl propionate ([C]MP4P) as test tracers, both of which are metabolic trapping tracers for measurement of brain acetylcholinesterase. The alpha-value in humans was then extrapolated from the alpha-value in rats by considering the differences between the species. The predicted human alpha-values were compared with those obtained from the kinetic analyses of human PET studies using [C]MP4A and [C]MP4P. RESULT: The alpha-values in the human brain cortex were predicted to be 0.51+/-0.1 for MP4A and 0.25+/-0.05 for MP4P. These results were close to values reported in other PET studies: 0.48+/-0.1 to 0.73+/-0.2 for MP4A and 0.15+/-0.04 to 0.18+/-0.04 for MP4P. CONCLUSION: The alpha-value predicted by this method would be used for practical selection or development of irreversible-type radiotracers for human use.
ESTHER : Ohya_2012_Nucl.Med.Commun_33_1019
PubMedSearch : Ohya_2012_Nucl.Med.Commun_33_1019
PubMedID: 22850605

Title : Reduced acetylcholinesterase activity in the fusiform gyrus in adults with autism spectrum disorders - Suzuki_2011_Arch.Gen.Psychiatry_68_306
Author(s) : Suzuki K , Sugihara G , Ouchi Y , Nakamura K , Tsujii M , Futatsubashi M , Iwata Y , Tsuchiya KJ , Matsumoto K , Takebayashi K , Wakuda T , Yoshihara Y , Suda S , Kikuchi M , Takei N , Sugiyama T , Irie T , Mori N
Ref : Arch Gen Psychiatry , 68 :306 , 2011
Abstract : CONTEXT: Both neuropsychological and functional magnetic resonance imaging studies have shown deficiencies in face perception in subjects with autism spectrum disorders (ASD). The fusiform gyrus has been regarded as the key structure in face perception. The cholinergic system is known to regulate the function of the visual pathway, including the fusiform gyrus. OBJECTIVES: To determine whether central acetylcholinesterase activity, a marker for the cholinergic system, is altered in ASD and whether the alteration in acetylcholinesterase activity, if any, is correlated with their social functioning. DESIGN: Using positron emission tomography and a radiotracer, N-[(11)C]methyl-4-piperidyl acetate ([(11)C]MP4A), regional cerebrocortical acetylcholinesterase activities were estimated by reference tissue-based linear least-squares analysis and expressed in terms of the rate constant k(3). Current and childhood autism symptoms in the adult subjects with ASD were assessed by the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised, respectively. Voxel-based analyses as well as region of interest-based methods were used for between-subject analysis and within-subject correlation analysis with respect to clinical variables. SETTING: Participants recruited from the community. PARTICIPANTS: Twenty adult subjects with ASD (14 male and 6 female; age range, 18-33 years; mean [SD] intelligence quotient, 91.6 [4.3]) and 20 age-, sex-, and intelligence quotient-matched healthy controls. RESULTS: Both voxel- and region of interest-based analyses revealed significantly lower [(11)C]MP4A k(3) values in the bilateral fusiform gyri of subjects with ASD than in those of controls (P < .05, corrected). The fusiform k(3) values in subjects with ASD were negatively correlated with their social disabilities as assessed by Autism Diagnostic Observation Schedule as well as Autism Diagnostic Interview-Revised. CONCLUSIONS: The results suggest that a deficit in cholinergic innervations of the fusiform gyrus, which can be observed in adults with ASD, may be related to not only current but also childhood impairment of social functioning.
ESTHER : Suzuki_2011_Arch.Gen.Psychiatry_68_306
PubMedSearch : Suzuki_2011_Arch.Gen.Psychiatry_68_306
PubMedID: 21383265

Title : Effect of radiolabeled metabolite elimination from the brain on the accuracy of cerebral enzyme activity estimation using positron emission tomography with substrate tracers - Ohya_2011_Neuroimage_56_1105
Author(s) : Ohya T , Okamura T , Nagai Y , Fukushi K , Irie T , Suhara T , Zhang MR , Fukumura T , Kikuchi T
Ref : Neuroimage , 56 :1105 , 2011
Abstract : Cerebral enzyme activity can be quantified using positron emission tomography (PET) in conjunction with a radiolabeled enzyme substrate. We investigated the relationship between the elimination rate (k(el)) of tracer metabolites from the brain and the precision of target enzyme activity estimation (k(3)). An initial simulation study indicated that the precision of k(3) estimates was highly dependent on k(el), and was characterized by several kinetic parameters including the ratio of k(el) and the efflux rate (k(2)) of authentic tracer (beta identical withk(el)/k(2)). The optimal tracer condition for high sensitivity was found to be beta<0.1. To verify the simulation results, we performed a PET study with a single monkey using two PET tracers, N-[(18)F]fluoroethylpiperidin-4-ylmethyl acetate ([(18)F]FEP-4MA) and N-[(11)C]methylpiperidin-4-yl acetate ([(11)C]MP4A). Both of these substrate type tracers were developed for measuring cerebral acetylcholinesterase activity. There was good retention of the radioactive metabolite of [(11)C]MP4A in the brain (k(el)=0.0036+/-0.0013 min(-1), beta=0.028), whereas that of [(18)F]FEP-4MA was eliminated from the brain (k(el)=0.012+/-0.0010 min(-1), beta=0.085). A non-linear least square analysis for simultaneous estimation of all parameters showed that the precision of the k(3) estimate for [(18)F]FEP-4MA was as high (7.4%) as that for [(11)C]MP4A (10%). These results indicate that tracers with metabolites that are eliminated from the brain at a slow rate (beta<0.1) may be useful for the quantitative measurement of target enzyme activity.
ESTHER : Ohya_2011_Neuroimage_56_1105
PubMedSearch : Ohya_2011_Neuroimage_56_1105
PubMedID: 21324368

Title : In vivo detection of neuropathologic changes in presymptomatic MAPT mutation carriers: a PET and MRI study - Miyoshi_2010_Parkinsonism.Relat.Disord_16_404
Author(s) : Miyoshi M , Shinotoh H , Wszolek ZK , Strongosky AJ , Shimada H , Arakawa R , Higuchi M , Ikoma Y , Yasuno F , Fukushi K , Irie T , Ito H , Suhara T
Ref : Parkinsonism Relat Disord , 16 :404 , 2010
Abstract : BACKGROUND: Microglial activation and disrupted neurotransmissions may herald symptomatic manifestations in neurodegenerative tauopathies. METHODS: We investigated microglial activation with [(11)C]DAA1106 positron emission tomography (PET), striatal dopaminergic function with l-[beta-(11)C]dopa PET, acetylcholinesterase (AChE) activity with [(11)C]N-methylpiperidin-4-yl acetate PET, and morphologic brain changes with MRI in three persons (aged 38-41 years) with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), who were presymptomatic gene carriers (PGCs) from an American kindred with pallidopontonigral degeneration. The results from these 3 PGCs were compared with [(11)C]DAA1106 PET results from age-matched 9 healthy volunteers (HV), and with l-[beta-(11)C]dopa and [(11)C]MP4A PET results from 10 HV. Values considered significant were more than 2 SDs greater or less than the normal control mean, as the number of subjects was small for group comparisons. RESULTS: Glial activities were increased in the frontal cortex of one PGC, the occipital cortex of two PGCs, and the posterior cingulate cortex of one PGC, although none of the PGCs showed overt glial activation in the brain. Only one of the PGCs showed reduced AChE activity in the temporo-parietal cortex. Three PGCs showed low dopamine synthesis rates in the putamen. Hippocampal atrophy was observed in two PGCs. CONCLUSIONS: Hippocampal atrophy and striatal dopaminergic dysfunction may be early disease processes in the pathogenesis of FTDP-17. Neuroinflammation may also be an in vivo signature of tau pathology at a prodromal stage, although current PET techniques may not constantly reveal it as the earliest neuroimaging abnormality.
ESTHER : Miyoshi_2010_Parkinsonism.Relat.Disord_16_404
PubMedSearch : Miyoshi_2010_Parkinsonism.Relat.Disord_16_404
PubMedID: 20452812

Title : Piperidine-4-methanthiol ester derivatives for a selective acetylcholinesterase assay - Kikuchi_2010_Biol.Pharm.Bull_33_702
Author(s) : Kikuchi T , Okamura T , Fukushi K , Irie T
Ref : Biol Pharm Bull , 33 :702 , 2010
Abstract : The activity of acetylcholinesterase (AChE) is measured to obtain pathological information about the cholinergic system in various disease states and to assess the effect of AChE inhibitors. Using Ellman's method that is commonly used in such examinations, butyrylcholinesterase inhibitors must be added to measure AChE-specific activity because of low selectivity of AChE toward traditional substrates; however, such inhibitors also inhibit AChE. Therefore, it is desirable to obtain an AChE selective substrate that can be used with the Ellman's method. Here, we synthesized novel AChE substrates, 1-methyl-4-acetylthiomethylpiperidine and 1,1-dimethyl-4-acetylthiomethylpiperidine, and evaluated the hydrolysis rate and AChE selectivity by comparison with the results obtained when traditional substrates were used. The hydrolysis rate of the novel compounds by human AChE was one order of magnitude lower than that of the traditional substrates, acetylthiocholine and acetyl-beta-methylthiocholine, whereas the hydrolysis rate using human butyrylcholinesterase was two orders of magnitude lower than that of the traditional substrates. This indicated that AChE showed selectivity towards the novel substrates which was one order of magnitude higher than that of the traditional substrates. The hydrolysis of the novel compounds in a rat cerebral cortical homogenate and a monkey whole blood was completely inhibited by 1 muM of the specific AChE inhibitor, 1,5-bis(4-allyldimethylammoniumphenyl)pentan-3-one, indicating the high specificity of AChE towards the novel substrates in a crude tissue sample. From these results, we conclude that the novel compounds developed would be suitable AChE-selective substrates for Ellman's method.
ESTHER : Kikuchi_2010_Biol.Pharm.Bull_33_702
PubMedSearch : Kikuchi_2010_Biol.Pharm.Bull_33_702
PubMedID: 20410609

Title : Use of a novel radiometric method to assess the inhibitory effect of donepezil on acetylcholinesterase activity in minimally diluted tissue samples - Kikuchi_2010_Br.J.Pharmacol_159_1732
Author(s) : Kikuchi T , Okamura T , Arai T , Obata T , Fukushi K , Irie T , Shiraishi T
Ref : British Journal of Pharmacology , 159 :1732 , 2010
Abstract : BACKGROUND AND PURPOSE: Cholinesterase inhibitors have been widely used for the treatment of patients with dementia. Monitoring of the cholinesterase activity in the blood is used as an indicator of the effect of the cholinesterase inhibitors in the brain. The selective measurement of cholinesterase with low tissue dilution is preferred for accurate monitoring; however, the methods have not been established. Here, we investigated the effect of tissue dilution on the action of cholinesterase inhibitors using a novel radiometric method with selective substrates, N-[(14)C]methylpiperidin-4-yl acetate ([(14)C]MP4A) and (R)-N- [(14)C]methylpiperidin-3-yl butyrate ([(14)C]MP3B_R), for AChE and butyrylcholinesterase (BChE) respectively. EXPERIMENTAL APPROACH: We investigated the kinetics of hydrolysis of [(14)C]-MP4A and [(14)C]-MP3B_R by cholinesterases, and evaluated the selectivity of [(14)C]MP4A and [(14)C]MP3B_R for human AChE and BChE, respectively, compared with traditional substrates. Then, IC(50) values of cholinesterase inhibitors in minimally diluted and highly diluted tissues were measured with [(14)C]MP4A and [(14)C]MP3B_R. KEY RESULTS: AChE and BChE activities were selectively measured as the first-order hydrolysis rates of [(14)C]-MP4A and [(14)C]MP3B_R respectively. The AChE selectivity of [(14)C]MP4A was an order of magnitude higher than traditional substrates used for the AChE assay. The IC(50) values of specific AChE and BChE inhibitors, donepezil and ethopropazine, in 1.2-fold diluted human whole blood were much higher than those in 120-fold diluted blood. In addition, the IC(50) values of donepezil in monkey brain were dramatically decreased as the tissue was diluted. CONCLUSIONS AND IMPLICATIONS: This method would effectively monitor the activity of cholinesterase inhibitors used for therapeutics, pesticides and chemical warfare agents.
ESTHER : Kikuchi_2010_Br.J.Pharmacol_159_1732
PubMedSearch : Kikuchi_2010_Br.J.Pharmacol_159_1732
PubMedID: 20401964

Title : Cholinergic imaging in corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia - Hirano_2010_Brain_133_2058
Author(s) : Hirano S , Shinotoh H , Shimada H , Aotsuka A , Tanaka N , Ota T , Sato K , Ito H , Kuwabara S , Fukushi K , Irie T , Suhara T
Ref : Brain , 133 :2058 , 2010
Abstract : Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [11C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6+/-5.9 years), 12 with progressive supranuclear palsy (68.5+/-4.1 years), eight with frontotemporal dementia (59.8+/-6.9 years) and 16 healthy controls (61.2+/-8.5 years). Two-tissue compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k3 value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k3 images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k3 images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k3 values) in the paracentral region, frontal, parietal and occipital cortices (P<0.05, cluster corrected). The group with progressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P<0.05, cluster corrected). The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity. Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P<0.001), 9.4% in progressive supranuclear palsy (P<0.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P<0.03) and increased by 3.3% in frontotemporal dementia (non-significant). Both corticobasal syndrome and progressive supranuclear palsy showed brain cholinergic deficits, but their distribution differed somewhat. Significant brain cholinergic deficits were not seen in frontotemporal dementia, which may explain the unresponsiveness of this condition to cholinergic modulation therapy.
ESTHER : Hirano_2010_Brain_133_2058
PubMedSearch : Hirano_2010_Brain_133_2058
PubMedID: 20558417

Title : In vivo evaluation of N-[18F]fluoroethylpiperidin-4ylmethyl acetate in rats compared with MP4A as a probe for measuring cerebral acetylcholinesterase activity - Kikuchi_2010_Synapse_64_209
Author(s) : Kikuchi T , Okamura T , Zhang MR , Fukushi K , Irie T
Ref : Synapse , 64 :209 , 2010
Abstract : [(11)C]MP4A is an established radioprobe for quantification of cerebral acetylcholinesterase (AChE) activity by positron emission tomography (PET) based on the kinetics of AChE-mediated metabolism and metabolite trapping. It has been used to assess the deficiency in cholinergic innervation in the brain of patients with dementia. Because (18)F has a longer half-life than (11)C, (18)F-labeled derivatives of [(11)C]MP4A allow delivery of the probe to other PET centers, making AChE measurement more widely applicable. Previously, N-[(18)F]fluoroethylpiperidin-4ylmethyl acetate ([(18)F]FEP-4MA) showed that the (18)F-labeled analog of MP4A possessed desirable properties for the quantification of cerebral AChE activity by PET. Here, we evaluated the in vivo kinetics of [(18)F]FEP-4MA and validated the responsiveness of brain uptake to AChE activity based on a mathematical model derived from the AChE-mediated trapping rationale and compared it with MP4A in rats. Almost all radioactivity in the brain was composed of [(18)F]FEP-4MA and the hydrolyzed metabolite at 0-60-min postinjection. When the authentic radioprobe was not observed in the brain, the regional (18)F uptake in the brain correlated well with regional MP4A uptake, and the elimination rate of (18)F from the brain was higher than that of the metabolite of MP4A. The responsiveness of regional (18)F uptake in the brain was examined by simultaneous assay of (18)F concentration, relative blood flow, and AChE activity. Regional (18)F uptake correlated with regional AChE activity as well as that of MP4A. Therefore, we concluded that [(18)F]FEP-4MA would be applicable to clinical PET study for quantifying cerebral AChE activity.
ESTHER : Kikuchi_2010_Synapse_64_209
PubMedSearch : Kikuchi_2010_Synapse_64_209
PubMedID: 19862687

Title : Estimation of plasma IC50 of donepezil for cerebral acetylcholinesterase inhibition in patients with Alzheimer disease using positron emission tomography - Ota_2010_Clin.Neuropharmacol_33_74
Author(s) : Ota T , Shinotoh H , Fukushi K , Kikuchi T , Sato K , Tanaka N , Shimada H , Hirano S , Miyoshi M , Arai H , Suhara T , Irie T
Ref : Clinical Neuropharmacology , 33 :74 , 2010
Abstract : OBJECTIVES: Estimate the value of in vivo plasma IC50 of donepezil, the concentration of donepezil in plasma that inhibits brain acetylcholinesterase (AChE) activity by 50% at the steady-state conditions of donepezil between the plasma and the brain. METHODS: N-[C] methylpiperidin-4-yl acetate ([C]MP4A) positron emission tomography was performed in 16 patients with probable Alzheimer disease (AD) before and during the treatment of donepezil (5 mg/day) with a mean interval of 5.3 months. The plasma IC50 value of donepezil was estimated from plasma donepezil concentrations and cerebral cortical mean AChE inhibition rates measured by positron emission tomography, using one-parameter model. RESULTS: Donepezil reduced AChE activity uniformly in the cerebral cortex compared with the baseline in each AD patient, and the mean reduction rate in the cerebral cortex was 34.6%. The donepezil concentrations in the plasma ranged from 18.5 to 43.9 ng/mL with a mean of 28.9 +/- 7.3 ng/mL. The plasma IC50 value was estimated to be 53.6 +/- 4.0 ng/mL. CONCLUSIONS: Once the plasma IC50 of donepezil is determined, the brain AChE inhibition rate could be estimated from the plasma concentration of donepezil in each subject based on the plasma IC50. Now that the mean donepezil concentrations in the plasma, when the patients took 5 mg/day, remained 28.9 ng/mL, approximately half of the plasma IC50, higher dose of donepezil might provide further benefits for patients with AD. This technique can be also applied to measure the in vivo plasma IC50 of other cholinesterase inhibitors such as rivastigmine and galantamine.
ESTHER : Ota_2010_Clin.Neuropharmacol_33_74
PubMedSearch : Ota_2010_Clin.Neuropharmacol_33_74
PubMedID: 19935404

Title : Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET - Shimada_2009_Neurology_73_273
Author(s) : Shimada H , Hirano S , Shinotoh H , Aotsuka A , Sato K , Tanaka N , Ota T , Asahina M , Fukushi K , Kuwabara S , Hattori T , Suhara T , Irie T
Ref : Neurology , 73 :273 , 2009
Abstract : OBJECTIVE: To characterize brain cholinergic deficits in Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB). METHODS: Participants included 18 patients with PD, 21 patients with PDD/DLB, and 26 healthy controls. The PD group consisted of nine patients with early PD, each with a disease duration of less than 3 years, five of whom were de novo PD patients, and nine patients with advanced PD, each with a disease duration greater than or equal to 3 years. The PDD/DLB group consisted of 10 patients with PDD and 11 patients with DLB. All subjects underwent PET scans with N-[11C]-methyl-4-piperidyl acetate to measure brain acetylcholinesterase (AChE) activity. Brain AChE activity levels were estimated voxel-by-voxel in a three-compartment analysis using the arterial input function, and compared among our subject groups through both voxel-based analysis using the statistical parametric mapping software SPM5 and volume-of-interest analysis. RESULTS: Among patients with PD, AChE activity was significantly decreased in the cerebral cortex and especially in the medial occipital cortex (% reduction compared with the normal mean = -12%) (false discovery rate-corrected p value <0.01). Patients with PDD/DLB, however, had even lower AChE activity in the cerebral cortex (% reduction = -27%) (p < 0.01). There was no significant difference between early PD and advanced PD groups or between DLB and PDD groups in the amount by which regional AChE activity in the brain was reduced. CONCLUSIONS: Brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. It begins in early Parkinson disease, and is more widespread and profound in both Parkinson disease with dementia and dementia with Lewy bodies.
ESTHER : Shimada_2009_Neurology_73_273
PubMedSearch : Shimada_2009_Neurology_73_273
PubMedID: 19474411

Title : PET study of brain acetylcholinesterase in cerebellar degenerative disorders - Hirano_2008_Mov.Disord_23_1154
Author(s) : Hirano S , Shinotoh H , Arai K , Aotsuka A , Yasuno F , Tanaka N , Ota T , Sato K , Fukushi K , Tanada S , Hattori T , Irie T
Ref : Movement Disordersord , 23 :1154 , 2008
Abstract : To elucidate characteristic changes of brain acetylcholinesterase (AChE) in cerebellar degenerative disorders. Eight patients with the cerebellar variant of multiple system atrophy (MSA-C), 7 patients with spinocerebellar ataxia type-3 (SCA-3), 3 patients with SCA-6, and 13 healthy age-matched volunteers participated in this study. Brain AChE activity was measured by [(11)C] N-methylpiperidin-4-yl propionate PET in all subjects. Brain AChE activities were significantly decreased in the thalamus (-27%) and the posterior lobe of cerebellar cortex (-36%) in patients with MSA-C and in the thalamus (-23%) in patients with SCA-3 compared with healthy controls (P < 0.01). Thalamic AChE activities of SCA-3 patients were negatively correlated with the unified Parkinson's disease rating scale motor subscore (P < 0.001). AChE activities were not significantly altered in the cerebral cortex in any disease group. Reduction of AChE activities in the thalamus and cerebellum in MSA and in the thalamus in SCA-3 suggest that cholinergic modulating drugs may have a role in the treatment of ataxia and other symptoms in these disorders.
ESTHER : Hirano_2008_Mov.Disord_23_1154
PubMedSearch : Hirano_2008_Mov.Disord_23_1154
PubMedID: 18412283

Title : Cerebral acetylcholinesterase imaging: development of the radioprobes - Kikuchi_2007_Curr.Top.Med.Chem_7_1790
Author(s) : Kikuchi T , Okamura T , Fukushi K , Takahashi K , Toyohara J , Okada M , Zhang MR , Irie T
Ref : Curr Top Med Chem , 7 :1790 , 2007
Abstract : Cerebral acetylcholinesterase (AChE) imaging is not only useful for diagnosis of dementia disorders but also for therapeutic monitoring of the effects of cholinesterase (ChE) inhibitors and for decision of the appropriate clinical dosage of newly developed ChE inhibitors. Several ChE inhibitors or the derivatives such as 1,2,3,4-tetrahydro-9-methylaminoacridine (MTHA), donepezil, physostigmine, CP126,998 and 2-fluoro-CP118,954 have been labeled with positron emitters for mapping cerebral AChE by positron emission tomography (PET). When [(11)C]MTHA or [(11)C]donepezil was injected in animals, the uptake poorly reflect the regional distribution of AChE in the brain because of high non-specific binding and/or less specific to AChE in vivo in the brain tissue. [(11)C]physostigmine, [(11)C]CP126,998 and 2-[(18)F]fluoro-CP118,954 were distributed corresponding well to the regional AChE activity in animals, and also former two probes were successfully applied to clinical PET trial. The other approach is measuring cerebral AChE activity with radiolabeled acetylcholine analogue substrates. We have developed the principle for measuring cerebral enzyme activity by PET and radiolabeled N-methylpiperidinyl esters for quantitative measurement of cerebral AChE activity. N-[(11)C]methylipiperidin-4-yl acetate (MP4A) and N-[(11)C]methylpiperidin-4-yl propionate (MP4P) have been used for clinical studies of other demented disorders including Alzheimer's disease (AD), and the probes have demonstrated not only the reduction of AChE activity in the cerebral cortex of patients with AD but also the inhibitory effects of donepezil and rivastigmine on AChE activity in the brain of AD patients. Following this succession, widely available [(18)F]-labeled derivatives of MP4A and MP4P have been developed based on the structure-activity relationships between AChE and piperidinol esters.
ESTHER : Kikuchi_2007_Curr.Top.Med.Chem_7_1790
PubMedSearch : Kikuchi_2007_Curr.Top.Med.Chem_7_1790
PubMedID: 17979787

Title : Preclinical investigation of the topical administration of phenserine: transdermal flux, cholinesterase inhibition, and cognitive efficacy - Utsuki_2007_J.Pharmacol.Exp.Ther_321_353
Author(s) : Utsuki T , Uchimura N , Irikura M , Moriuchi H , Holloway HW , Yu QS , Spangler EL , Mamczarz J , Ingram DK , Irie T , Greig NH
Ref : Journal of Pharmacology & Experimental Therapeutics , 321 :353 , 2007
Abstract : Phenserine (PS) was designed as a selective acetylcholinesterase (AChE) inhibitor, with a tartrate form (PST) for oral administration in mild to moderate Alzheimer's disease (AD). Recent phase 3 trials of PST in Europe indicate that any clinically relevant activity of PST may be limited by its duration of action. Like many oral drugs, bioavailability and plasma concentrations of PST are regulated by hepatic and gastrointestinal first-pass effects. To minimize the kinetic limitations of first-pass metabolism, transdermal formulations of PS and PST (ointment/patch) were developed and characterized in vitro and in vivo. Initial in vitro kinetic characterization of PS or PST formulations used a diffusion cell chamber and skin samples isolated from hairless mice. Liquid paraffin and fatty alcohol/propylene glycol (FAPG) were found to be suitable vehicles for ointment formulation. Addition of a penetration enhancer, 1-[2-(decylthio)ethyl]-azacyclopentane-2-one (HPE-101), improved stratum corneum permeability. Application of the optimal formulation of PS/HPE-101/FAPG to the shaved back of rats resulted in significantly lowered plasma and brain AChE activities and improved cognitive performance in animals with scopolamine-induced cognitive impairment. These results suggest that the transdermal application of AChE inhibitors may represent an effective therapeutic strategy for AD. Particular benefits over oral therapies might include avoiding first-pass metabolic effects and improved dosing compliance.
ESTHER : Utsuki_2007_J.Pharmacol.Exp.Ther_321_353
PubMedSearch : Utsuki_2007_J.Pharmacol.Exp.Ther_321_353
PubMedID: 17255466

Title : Brain acetylcholinesterase activity in FTDP-17 studied by PET -
Author(s) : Hirano S , Shinotoh H , Kobayashi T , Tsuboi Y , Wszolek ZK , Aotsuka A , Tanaka N , Ota T , Fukushi K , Tanada S , Irie T
Ref : Neurology , 66 :1276 , 2006
PubMedID: 16636254

Title : Estimation of plasma IC50 of donepezil hydrochloride for brain acetylcholinesterase inhibition in monkey using N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) and PET - Shiraishi_2005_Neuropsychopharmacology_30_2154
Author(s) : Shiraishi T , Kikuchi T , Fukushi K , Shinotoh H , Nagatsuka S , Tanaka N , Ota T , Sato K , Hirano S , Tanada S , Iyo M , Irie T
Ref : Neuropsychopharmacology , 30 :2154 , 2005
Abstract : Donepezil hydrochloride is a potent and selective inhibitor for brain acetylcholinesterase (AChE) and is currently used worldwide for the treatment of Alzheimer's disease. Until now, there is no in vivo study on the relation between the plasma concentration and the brain AChE inhibition. The purpose of this study was to estimate in vivo plasma IC(50) of donepezil in living monkeys by measuring plasma donepezil concentration (LC/MS/MS) and brain AChE activity with positron emission tomography (PET) and N-[(11)C]methylpiperidin-4-yl acetate, which is an acetylcholine analog recently developed by us for quantifying in vivo brain AChE activity. PET scans with donepezil at two doses, 100 microg/kg (donepezil-1; N=5) or 250 microg/kg (donepezil-2; N=5), were performed using the same monkeys at 4-week intervals. Before each PET scan, baseline PET scans (N=10 in total) were performed without donepezil. The plasma donepezil concentrations 14 min after intravenous injection were proportional to the doses, 17.2+/-2.9 ng/ml (donepezil-1) and 44.0+/-5.0 ng/ml (donepezil-2), and the mean AChE inhibitions in four neocortical regions as evaluated by PET were also dose-dependent, 27% (donepezil-1) and 53% (donepezil-2). In IC(50) estimation, measured plasma donepezil concentrations were corrected for the change during PET scan. The IC(50) values (estimate+/-SE) were 42+/-9.0 (ng/ml; donepezil-1), 34+/-3.2 (donepezil-2), and 37+/-4.1 (combined data). The present method may be useful for in vivo evaluation of other AChE inhibitors and novel drugs.
ESTHER : Shiraishi_2005_Neuropsychopharmacology_30_2154
PubMedSearch : Shiraishi_2005_Neuropsychopharmacology_30_2154
PubMedID: 15920507

Title : N-[18F] fluoroethylpiperidin-4ylmethyl acetate, a novel lipophilic acetylcholine analogue for PET measurement of brain acetylcholinesterase activity - Kikuchi_2005_J.Med.Chem_48_2577
Author(s) : Kikuchi T , Zhang MR , Ikota N , Fukushi K , Okamura T , Suzuki K , Arano Y , Irie T
Ref : Journal of Medicinal Chemistry , 48 :2577 , 2005
Abstract : The reduction of acetylcholinesterase (AChE) activity in the brain has been measured in dementia disorders such as Alzheimer's disease and dementia with Lewy bodies using (11)C-labeled acetylcholine analogues, N-[(11)C]methylpiperidin-4-yl acetate and propionate, and positron emission tomography (PET). Our aim was to develop an (18)F-labeled acetylcholine analogue useful for brain AChE mapping with PET, since (18)F, with a longer half-life, has advantages over (11)C. In a preliminary study, a series of N-[(14)C]ethylpiperidin-3-yl or -4-ylmethanol esters (acetyl and propionyl esters) were newly designed and evaluated in vitro regarding the reactivity with and specificity to AChE using purified human enzymes, leading to a novel (18)F-labeled acetylcholine analogue, N-[(18)F]fluoroethylpiperidin-4-ylmethyl acetate. In rat experiments, the (18)F-labeled candidate showed desirable properties for PET AChE measurement: high brain uptake of the authentic ester, high AChE specificity, a moderate hydrolysis rate, and low membrane permeability (metabolic trapping) of the metabolite.
ESTHER : Kikuchi_2005_J.Med.Chem_48_2577
PubMedSearch : Kikuchi_2005_J.Med.Chem_48_2577
PubMedID: 15801847

Title : A simple method for the detection of abnormal brain regions in Alzheimer's disease patients using [11C]MP4A: comparison with [123I]IMP SPECT - Ota_2004_Ann.Nucl.Med_18_187
Author(s) : Ota T , Shinotoh H , Fukushi K , Nagatsuka S , Namba H , Iyo M , Aotsuka A , Tanaka N , Sato K , Shiraishi T , Tanada S , Arai H , Irie T
Ref : Ann Nucl Med , 18 :187 , 2004
Abstract : We have developed a radiolabeled lipophilic acetylcholine analogue, N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) to measure brain acetylcholinesterase (AChE) activity by positron emission tomography (PET) in vivo. Aiming to develop a new SPECT tracer similar to MP4A, we first proposed a simple method for diagnosing Alzheimer's disease (AD) using [11C]MP4A PET. We performed [11C]MP4A PET and N-isopropyl [123I]iodoamphetamine ([123I]IMP) SPECT in 13 patients with AD and in 17 normal controls (NC). We calculated the ratio of radioactivity of the cortical region of interest (ROI) to that of the cerebellum measured with [11C]MP4A PET (MP4A ratio) and the ratio of regional cerebral blood flow (rCBF) to that of the cerebellum measured with [123I]IMP SPECT (IMP ratio). Eleven cortical ROIs were placed in the frontal, sensorimotor, temporal, parietal, and occipital cortices in both hemispheres and in the posterior cingulate cortex, and z-score was calculated in each ROI in patients with AD compared with NC. When the z-score was 2 or more in a ROI, it was defined as a positive ROI. When a patient had 3 or more positive ROIs, the patient was diagnosed as having AD. The reduction in the MP4A ratio was greater than that in the IMP ratio in all cortical ROIs except for in the right parietal cortex and cingulate cortex in patients with AD. MP4A ratio method showed 92% sensitivity and the IMP ratio method 69% sensitivity for the diagnosis of AD. These results encourage us to develop a new SPECT tracer similar to MP4A for the diagnosis of AD.
ESTHER : Ota_2004_Ann.Nucl.Med_18_187
PubMedSearch : Ota_2004_Ann.Nucl.Med_18_187
PubMedID: 15233279

Title : Acetylcholinesterase imaging: its use in therapy evaluation and drug design - Shinotoh_2004_Curr.Pharm.Des_10_1505
Author(s) : Shinotoh H , Fukushi K , Nagatsuka S , Irie T
Ref : Curr Pharm Des , 10 :1505 , 2004
Abstract : Several cholinesterase (ChE) inhibitors have been labeled with carbon-11 for visualizing binding sites on acetylcholinesterase (AChE) by positron emission tomography (PET). Following intravenous injection of 1,2,3,4-tetrahydro-9-[(11)C]methylaminoacridine or [(11)C]donepezil, however, the radioactivity distribution does not reflect the regional distribution of AChE in the brain of animals, probably because these compounds have high non-specific binding and/or other specific binding sites in vivo in the brain. PET studies with [(11)C]physostigmine and [(11)C]CP-126,998 in the brain of healthy subjects have shown a radioactivity distribution corresponding to the regional distribution of AChE activity measured in postmortem human brains. These radiotracers may be useful for measuring the occupancy of binding sites on AChE by AChE inhibitors, and for investigating the cerebral pharmacokinetics of such therapeutic drugs. An alternative approach to map AChE is the use of acetylcholine analogue substrates. We have developed N-methylpiperidinyl esters labeled with carbon-11 for quantitative measurement of AChE activity. Currently, two N-[(11)C]methylpiperidine esters, N-[(11)C]methylipiperidin-4-ylacetate (MP4A) and N-[(11)C]methylpiperidin-4-yl propionate (MP4P or PMP), have been used for clinical studies of Alzheimer's disease and other neurodegenerative diseases. Both [(11)C]MP4A- and [(11)C]MP4P-PET have demonstrated not only the reduction of AChE activity in the cerebral cortex of patients with Alzheimer's disease (AD) but also the inhibitory effects of donepezil and rivastigmine on AChE activity in the brain of AD patients. AChE imaging should prove useful for therapeutic monitoring of the effects of ChE inhibitors, including determination of the appropriate clinical doses of newly developed compounds, and can thus prompt the development of novel drugs targeting AChE.
ESTHER : Shinotoh_2004_Curr.Pharm.Des_10_1505
PubMedSearch : Shinotoh_2004_Curr.Pharm.Des_10_1505
PubMedID: 15134572

Title : N-[18F]fluoroethylpiperidin-4-ylmethyl butyrate: a novel radiotracer for quantifying brain butyrylcholinesterase activity by positron emission tomography - Kikuchi_2004_Bioorg.Med.Chem.Lett_14_1927
Author(s) : Kikuchi T , Zhang MR , Ikota N , Fukushi K , Okamura T , Suzuki K , Arano Y , Irie T
Ref : Bioorganic & Medicinal Chemistry Lett , 14 :1927 , 2004
Abstract : In Alzheimer's disease, cerebral cortical butyrylcholinesterase (BChE) activity is reported to be elevated. Our aim was to develop a novel (18)F-labeled tracer for quantifying cerebral BChE activity by positron emission tomography. With in vitro screening of N-[(14)C]ethylpiperidin-3- and 4-ylmethyl esters, N-[(14)C]ethylpiperidin-4-ylmethyl butyrate was selected as a lead for (18)F-labeling, affording N-[(18)F]fluoroethylpiperidin-4-ylmethyl butyrate. The (18)F-labeled butyrate showed the required properties for in vivo BChE measurement, that is, the lipophilic nature of the authentic ester, high specificity to BChE, a moderate hydrolysis rate, and the hydrophilic nature of the metabolite.
ESTHER : Kikuchi_2004_Bioorg.Med.Chem.Lett_14_1927
PubMedSearch : Kikuchi_2004_Bioorg.Med.Chem.Lett_14_1927
PubMedID: 15050629

Title : Evaluation of simplified kinetic analyses for measurement of brain acetylcholinesterase activity using N-[11C]Methylpiperidin-4-yl propionate and positron emission tomography - Sato_2004_J.Cereb.Blood.Flow.Metab_24_600
Author(s) : Sato K , Fukushi K , Shinotoh H , Nagatsuka S , Tanaka N , Aotsuka A , Ota T , Shiraishi T , Tanada S , Iyo M , Irie T
Ref : Journal of Cerebral Blood Flow & Metabolism , 24 :600 , 2004
Abstract : The applicability of two reference tissue-based analyses without arterial blood sampling for the measurement of brain regional acetylcholinesterase (AChE) activity using N-[11C]methylpiperidin-4-yl propionate ([11C]MP4P) was evaluated in 12 healthy subjects. One was a linear least squares analysis derived from Blomqvist's equation, and the other was the analysis of the ratio of target-tissue radioactivity relative to reference-tissue radioactivity proposed by Herholz and coworkers. The standard compartment analysis using arterial input function provided reliable quantification of k3 (an index of AChE activity) estimates in regions with low (neocortex and hippocampus), moderate (thalamus), and high (cerebellum) AChE activity with a coefficient of variation (COV) of 12% to 19%. However, the precise k3 value in the striatum, where AChE activity is the highest, was not obtained. The striatum was used as a reference because its time-radioactivity curve was proportional to the time integral of the arterial input function. Reliable k3 estimates were also obtained in regions with low-to-moderate AChE activity with a COV of less than 21% by striatal reference analyses, though not obtained in the cerebellum. Shape analysis, the previous method of direct k3 estimation from the shape of time-radioactivity data, gave k3 estimates in the cortex and thalamus with a somewhat larger COV. In comparison with the standard analysis, a moderate overestimation of k3 by 9% to 18% in the linear analysis and a moderate underestimation by 2% to 13% in the Herholz method were observed, which were appropriately explained by the results of computer simulation. In conclusion, simplified kinetic analyses are practical and useful for the routine analysis of clinical [11C]MP4P studies and are nearly as effective as the standard analysis for detecting regions with abnormal AChE activity.
ESTHER : Sato_2004_J.Cereb.Blood.Flow.Metab_24_600
PubMedSearch : Sato_2004_J.Cereb.Blood.Flow.Metab_24_600
PubMedID: 15181367

Title : The amygdala and Alzheimer's disease: positron emission tomographic study of the cholinergic system - Shinotoh_2003_Ann.N.Y.Acad.Sci_985_411
Author(s) : Shinotoh H , Fukushi K , Nagatsuka S , Tanaka N , Aotsuka A , Ota T , Namba H , Tanada S , Irie T
Ref : Annals of the New York Academy of Sciences , 985 :411 , 2003
Abstract : The primary transmitter deficit is cholinergic in Alzheimer's disease (AD), and the amygdala receives a major cholinergic projection from the nucleus basalis of Meynert (Ch4), which may play an important role in the retention of affective conditioning and/or memory consolidation. We measured brain acetylcholinesterase (AChE) activity in 54 patients with AD and in 22 normal controls by positron emission tomography and N-[(11)C]methylpiperidin-4-yl acetate to characterize the cholinergic pathology in AD. The k(3) values were calculated as an index of AChE activity in a three-compartment model analysis using the metabolite-corrected arterial input function. The k(3) values were highly significantly reduced by 20% in the cerebral neocortex (P <0.0001 in the two-tailed t test), 14% in the hippocampus (P <0.001), and 33% in the amygdala (P <0.0001) in AD patients compared with normal controls. The k(3) values were significantly correlated with the Mini-Mental State Examination scores in both the cerebral cortex (P <0.001) and the amygdala (P <0.05) in AD patients, supporting the cholinergic hypothesis of cognitive dysfuncion in AD. Further studies are required, however, to elucidate the specific role of the cholinergic deficit in the amygdala in the emotional and behavioral symptoms in AD.
ESTHER : Shinotoh_2003_Ann.N.Y.Acad.Sci_985_411
PubMedSearch : Shinotoh_2003_Ann.N.Y.Acad.Sci_985_411
PubMedID: 12724174

Title : N-[18F]fluoroethyl-4-piperidyl acetate ([18F]FEtP4A): A PET tracer for imaging brain acetylcholinesterase in vivo - Zhang_2003_Bioorg.Med.Chem_11_2519
Author(s) : Zhang MR , Furutsuka K , Maeda J , Kikuchi T , Kida T , Okauchi T , Irie T , Suzuki K
Ref : Bioorganic & Medicinal Chemistry , 11 :2519 , 2003
Abstract : N-[(18)F]Fluoroethyl-4-piperidyl acetate ([(18)F]FEtP4A) was synthesized and evaluated as a PET tracer for imaging brain acetylcholinesterase (AchE) in vivo. [(18)F]FEtP4A was previously prepared by reacting 4-piperidyl acetate (P4A) with 2-[(18)F]fluoroethyl bromide ([(18)F]FEtBr) at 130 degrees C for 30 min in 37% radiochemical yield using an automated synthetic system. In this work, [(18)F]FEtP4A was synthesized by reacting P4A with 2-[(18)F]fluoroethyl iodide ([(18)F]FEtI) or 2-[(18)F]fluoroethyl triflate ([(18)F]FEtOTf in improved radiochemical yields, compared with [(18)F]FEtBr under the corresponding condition. Ex vivo autoradiogram of rat brain and PET summation image of monkey brain after iv injection of [(18)F]FEtP4A displayed a high radioactivity in the striatum, a region with the highest AchE activity in the brain. Moreover, the distribution pattern of (18)F radioactivity was consistent with that of AchE in the brain: striatum>frontal cortex>cerebellum. In the rat and monkey plasma, two radioactive metabolites were detected. However, their presence might not preclude the imaging studies for AchE in the brain, because they were too hydrophilic to pass the blood-brain barrier and to enter the brain. In the rat brain, only [(18)F]fluoroethyl-4-piperidinol ([(18)F]FEtP4OH) was detected at 30 min postinjection. The hydrolytic [(18)F]FEtP4OH displayed a slow washout and a long retention in the monkey brain until the PET experiment (120 min). Although [(18)F]FEtP4A is a potential PET tracer for imaging AchE in vivo, its lower hydrolytic rate and lower specificity for AchE than those of [(11)C]MP4A may limit its usefulness for the quantitative measurement for AchE in the primate brain.
ESTHER : Zhang_2003_Bioorg.Med.Chem_11_2519
PubMedSearch : Zhang_2003_Bioorg.Med.Chem_11_2519
PubMedID: 12757720

Title : Involvement of calmodulin inhibition in analgesia induced with low doses of intrathecal trifluoperazine - Golbidi_2002_Jpn.J.Pharmacol_88_151
Author(s) : Golbidi S , Moriuchi H , Irie T , Ghafghazi T , Hajhashemi V
Ref : Japanese Journal of Pharmacology , 88 :151 , 2002
Abstract : We examined which of the known properties of trifluoperazine, including calmodulin inhibition, are involved in its analgesic effect. Furthermore, we tried to find any possible interaction between opioidergic system and calmodulin inhibition-induced analgesia. Intrathecal trifluoperazine (1, 10, 100 microg) showed a biphasic effect in the formalin test; i.e., analgesia at relatively low doses (1, 10 microg) and hyperalgesia at a high dose (100 microg). No analgesic effects were observed after intrathecal injection of sulpiride (1, 10, 100 microg), atropine (0.1, 1, 10 microg), phentolamine (0.1, 1, 10 microg) and brompheniramine (0.1, 1, 10 microg). Meanwhile, intrathecal calmidazolium (10, 50, 250 microg) induced a dose-dependent analgesia. Histamine (1 microg), physostigmine (1 microg), bromocriptine (1 microg) and norepinephrine (1 microg) did not affect trifluoperazine-induced analgesia. Calcium (20 microg) attenuated the antinociceptive effect of trifluoperazine and inhibited the analgesic effect of calmidazolium. Finally, naloxone (2 mg/kg) decreased trifluoperazine-induced antinociception but did not have any effects on calmidazolium-induced analgesia. We concluded that calmodulin inhibition may be involved in the analgesia produced by trifluoperazine. With increasing doses of trifluoperazine, the algesic effect seems to overcome the analgesic effect. It is also suggested that the opioidergic system does not interact with calmodulin inhibition-induced analgesia even though this system has a possible role in trifluoperazine-induced analgesia.
ESTHER : Golbidi_2002_Jpn.J.Pharmacol_88_151
PubMedSearch : Golbidi_2002_Jpn.J.Pharmacol_88_151
PubMedID: 11928715

Title : Positron emission tomography: quantitative measurement of brain acetylcholinesterase activity using radiolabeled substrates - Namba_2002_Methods_27_242
Author(s) : Namba H , Fukushi K , Nagatsuka S , Iyo M , Shinotoh H , Tanada S , Irie T
Ref : Methods , 27 :242 , 2002
Abstract : A new method for quantitative measurement of brain acetylcholinesterase (AChE) activity in living human brain using positron emission tomography (PET) is described. We tested several radiolabeled lipophilic acetylcholine analogs, e.g., N-methylpiperidyl esters, which readily entered the brain via the blood-brain barrier, were hydrolyzed selectively by AChE, and were then trapped in the brain. Among them, and tested and N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) was chosen as the tracer for PET. Quantitative measurement of cortical AChE was accomplished by fitting the time course of cerebral radioactivity concentration measured by PET and the metabolite-corrected arterial plasma input function using a nonlinear least-squares fitting method. Normal control studies of subjects with a wide range in age (24-89 years) showed no decrease in AChE activity in the cerebral cortex with age. Studies on patients with Alzheimer's disease demonstrated a widespread reduction of AChE activity in the cerebral cortex (more profound in early-onset than in late-onset Alzheimer's disease). Parkinson's disease and progressive supranuclear palsy, clinically similar disorders, could be differentiated with [11C]MP4A/PET studies. Simple methods without using an arterial input function are also proposed. The method provides a quantitative measure of the cholinergic aspect of brain function and proved to be useful in diagnosis of neurodegenerative disorders including Alzheimer's disease.
ESTHER : Namba_2002_Methods_27_242
PubMedSearch : Namba_2002_Methods_27_242
PubMedID: 12183113

Title : Synthesis and preliminary evaluation of [18F]FEtP4A, a promising PET tracer for mapping acetylcholinesterase in vivo - Zhang_2002_Nucl.Med.Biol_29_463
Author(s) : Zhang MR , Tsuchiyama A , Haradahira T , Furutsuka K , Yoshida Y , Kida T , Noguchi J , Irie T , Suzuki K
Ref : Nucl Med Biol , 29 :463 , 2002
Abstract : N-[18F]Fluoroethyl-4-piperidyl acetate ([18F]FEtP4A), an analog of [11C]MP4A for mapping brain acetylcholineseterase (AchE) activity, was prepared by reacting 4-piperidyl acetate (P4A) with [18F]fluoroethyl bromide ([18F]FEtBr) using a newly developed automated system. Preliminary evaluation showed that the initial uptake of [18F]FEtP4A in the mouse brain was > 8% injected dose/g tissue. The distribution pattern of [18F]FEtP4A in the brain was striatum>cerebral cortex>cerebellum within 10-120 min post-injection, which reflected the distribution rank pattern of AchE activity in the brain. Moreover, chemical analysis of in vivo radioactive metabolites in the mouse brain indicated that 83% of [18F]FEtP4A was hydrolyzed to N-[18F]fluoroethyl-4-piperidinol ([18F]FEtP4OH) after 1 min intravenous injection. From these results, [18F]FEtP4A may become a promising PET tracer for mapping the AchE in vivo.
ESTHER : Zhang_2002_Nucl.Med.Biol_29_463
PubMedSearch : Zhang_2002_Nucl.Med.Biol_29_463
PubMedID: 12031881

Title : Effect of donepezil on brain acetylcholinesterase activity in patients with AD measured by PET - Shinotoh_2001_Neurology_56_408
Author(s) : Shinotoh H , Aotsuka A , Fukushi K , Nagatsuka S , Tanaka N , Ota T , Tanada S , Irie T
Ref : Neurology , 56 :408 , 2001
Abstract : Acetylcholinesterase (AChE) activities in the brain of three patients with AD were measured once before and once during donepezil treatment (5 mg/d in two patients, 3 mg/d in one patient) using PET and N-[11C]methylpiperidin-4-yl acetate. Donepezil reduced k(3) values, an index of AChE activity, in the cerebral cortex by 39 +/- 5%. All patients showed some degree of symptomatic improvement, and it was concluded that this improvement was likely caused by improved cholinergic activity by inhibition of AChE in the brain.
ESTHER : Shinotoh_2001_Neurology_56_408
PubMedSearch : Shinotoh_2001_Neurology_56_408
PubMedID: 11171913

Title : 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 - Tanaka_2001_J.Cereb.Blood.Flow.Metab_21_295
Author(s) : Tanaka N , Fukushi K , Shinotoh H , Nagatsuka S , Namba H , Iyo M , Aotsuka A , Ota T , Tanada S , Irie T
Ref : Journal of Cerebral Blood Flow & Metabolism , 21 :295 , 2001
Abstract : 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.
ESTHER : Tanaka_2001_J.Cereb.Blood.Flow.Metab_21_295
PubMedSearch : Tanaka_2001_J.Cereb.Blood.Flow.Metab_21_295
PubMedID: 11295884

Title : 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 - Nagatsuka_2001_J.Cereb.Blood.Flow.Metab_21_1354
Author(s) : Nagatsuka Si S , Fukushi K , Shinotoh H , Namba H , Iyo M , Tanaka N , Aotsuka A , Ota T , Tanada S , Irie T
Ref : Journal of Cerebral Blood Flow & Metabolism , 21 :1354 , 2001
Abstract : 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.
ESTHER : Nagatsuka_2001_J.Cereb.Blood.Flow.Metab_21_1354
PubMedSearch : Nagatsuka_2001_J.Cereb.Blood.Flow.Metab_21_1354
PubMedID: 11702050

Title : Progressive loss of cortical acetylcholinesterase activity in association with cognitive decline in Alzheimer's disease: a positron emission tomography study - Shinotoh_2000_Ann.Neurol_48_194
Author(s) : Shinotoh H , Namba H , Fukushi K , Nagatsuka S , Tanaka N , Aotsuka A , Ota T , Tanada S , Irie T
Ref : Annals of Neurology , 48 :194 , 2000
Abstract : We measured brain acetylcholinesterase activity in 30 patients with Alzheimer's disease (AD) and 14 age-matched controls by positron emission tomography (PET) and using a carbon 11-labeled acetylcholine analogue. Seven AD patients had repeat PET scans. The k3 values were calculated as an index of acetylcholinesterase activity in a three-compartment analysis using the metabolite corrected arterial input function. Twenty-eight of the 30 AD patients (14 each in the early and late onset subgroups) were retained in the study so as to equalize the range and average severity of cognitive impairment within the early and late onset subgroups. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala in the early onset AD patients, although the k3 values were significantly reduced only in the temporoparietal cortex and amygdala in the late onset AD patients. In the longitudinal study, all 7 repeat AD patients showed further reduction of cortical k3 values in the second PET scans, with a mean interval of 2 years, suggesting a progressive loss of the ascending cholinergic system from the nucleus basalis of Meynert in AD. In 37 AD patients, there was a highly significant correlation between the cortical k3 values and Mini-Mental State Examination scores, supporting the cholinergic hypothesis in AD.
ESTHER : Shinotoh_2000_Ann.Neurol_48_194
PubMedSearch : Shinotoh_2000_Ann.Neurol_48_194
PubMedID: 10939570

Title : Brain acetylcholinesterase activity in Alzheimer disease measured by positron emission tomography - Shinotoh_2000_Alzheimer.Dis.Assoc.Disord_14 Suppl 1_S114
Author(s) : Shinotoh H , Namba H , Fukushi K , Nagatsuka S , Tanaka N , Aotsuka A , Tanada S , Irie T
Ref : Alzheimer Disease & Associated Disorders , 14 Suppl 1 :S114 , 2000
Abstract : Brain acetylcholinesterase activity was measured in 14 patients with Alzheimer disease and 14 age-matched control subjects by positron emission tomography with a radioactive acetylcholine analogue. Kinetic analysis was performed to calculate k3, an index of acetylcholinesterase activity. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala of all patients with Alzheimer disease, suggesting a loss of cholinergic innervation from the basal forebrain. Most profound reductions of k3 values were observed in the temporal (-30%) and parietal cortices (-31%), although reductions of k3 values were relatively uniform in the cerebral neocortex. This technique may be a powerful tool for early diagnosis of Alzheimer disease and also for therapeutic monitoring of acetylcholinesterase inhibitors in Alzheimer disease.
ESTHER : Shinotoh_2000_Alzheimer.Dis.Assoc.Disord_14 Suppl 1_S114
PubMedSearch : Shinotoh_2000_Alzheimer.Dis.Assoc.Disord_14 Suppl 1_S114
PubMedID: 10850739

Title : Human cerebral acetylcholinesterase activity measured with positron emission tomography: procedure, normal values and effect of age - Namba_1999_Eur.J.Nucl.Med_26_135
Author(s) : Namba H , Iyo M , Fukushi K , Shinotoh H , Nagatsuka S , Suhara T , Sudo Y , Suzuki K , Irie T
Ref : Eur J Nucl Med , 26 :135 , 1999
Abstract : The regional cerebral metabolic rate of [11C]N-methyl-4-piperidyl acetate, which is nearly proportional to regional cerebral acetylcholinesterase (AChE) activity, was measured by dynamic positron emission tomography in 20 healthy subjects with a wide age range (24-89 years). Quantitative measurement was achieved using a kinetic model which consisted of arterial plasma and cerebral tissue compartments. The plasma input function was obtained using thin-layer chromatography and an imaging phosphor plate system at frequent sampling intervals to catch the rapid metabolism of the tracer in the blood. The distribution of the rate constant k3, an index of AChE activity, agreed well with reported post-mortem AChE distribution in the cerebral cortex (0.067-0.097 min-1) and thalamus (0.268 min-1), where AChE activity was low to moderate. The k3 values in the striatum and cerebellum, where AChE activity was very high, did not respond linearly to AChE activity because of increased flow dependency. No significant effect of age was found on AChE activity of the cerebral cortex, suggesting that the ascending central cholinergic system is preserved in normal aging. This study has shown that quantitative measurement of enzyme activity in the living brain is possible through appropriate modelling of tracer kinetics and accurate measurement of the input function. The method should be applicable to patients with Alzheimer's disease and those with other kinds of dementia whose central cholinergic system has been reported to be disturbed.
ESTHER : Namba_1999_Eur.J.Nucl.Med_26_135
PubMedSearch : Namba_1999_Eur.J.Nucl.Med_26_135
PubMedID: 9933347

Title : Positron emission tomographic measurement of acetylcholinesterase activity reveals differential loss of ascending cholinergic systems in Parkinson's disease and progressive supranuclear palsy - Shinotoh_1999_Ann.Neurol_46_62
Author(s) : Shinotoh H , Namba H , Yamaguchi M , Fukushi K , Nagatsuka S , Iyo M , Asahina M , Hattori T , Tanada S , Irie T
Ref : Annals of Neurology , 46 :62 , 1999
Abstract : We measured brain acetylcholinesterase activity in 16 patients with Parkinson's disease (PD), 12 patients with progressive supranuclear palsy (PSP), and 13 age-matched controls, using N-methyl-4-[11C]piperidyl acetate and positron emission tomography. Kinetic analysis was performed to calculate k3, an index of acetylcholinesterase activity. In PD patients, there was a significant reduction (-17%) of cerebral cortical k3 compared with normal controls, whereas there was only a nonsignificant reduction (-10%) of cortical k3 in PSP patients. However, there was a prominent reduction (-38%) of thalamic k3 in PSP patients compared with normal controls, whereas there was only a nonsignificant reduction (-13%) of thalamic k3 in PD patients. The results suggest that there is a loss of cholinergic innervation to the cerebral cortex in association with cholinergic innervation to the thalamus in PD, whereas there is a preferential loss of cholinergic innervation to the thalamus in PSP. When the thalamic to cerebral cortical k3 ratio was taken for each subject, PD and PSP were separated, suggesting that positron emission tomography measurement of acetylcholinesterase activity may be useful for differentiating the two similar disorders.
ESTHER : Shinotoh_1999_Ann.Neurol_46_62
PubMedSearch : Shinotoh_1999_Ann.Neurol_46_62
PubMedID: 10401781

Title : Preserved acetylcholinesterase activity in aged cerebral cortex [letter] -
Author(s) : Namba H , Iyo M , Shinotoh H , Nagatsuka S , Fukushi K , Irie T
Ref : Lancet , 351 :881 , 1998
PubMedID: 9525373

Title : Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer's disease - Iyo_1997_Lancet_349_1805
Author(s) : Iyo M , Namba H , Fukushi K , Shinotoh H , Nagatsuka S , Suhara T , Sudo Y , Suzuki K , Irie T
Ref : Lancet , 349 :1805 , 1997
Abstract : BACKGROUND: Acetylcholinesterase activity, a marker for degeneration of the central cholinergic system, has consistently been reported, in necropsy brain studies, to be reduced in the cerebral cortex of patients with Alzheimer's disease. We have shown regional acetylcholinesterase activity in vivo in rodent and primate brains with radioactive acetylcholine analogues. In the present study, we used one of the analogues to map acetylcholinesterase activity in the brains of living people. METHODS: Positron emission tomography (PET) and a radiolabelled acetylcholine analogue with high hydrolytic specificity to acetylcholinesterase [11C]N-methyl-4-piperidyl acetate (MP4A), was used in eight elderly healthy controls and five patients with Alzheimer's disease who had mild dementia. All participants were given an intravenous injection of [11C]MP4A and then sequential patterns of radioactivity in various brain regions were obtained by PET. Time courses of [11C]MP4A concentration in arterial blood were also measured to obtain an input function. A three-compartment model was used to estimate regional acetylcholinesterase activity in the brain. FINDINGS: The estimated acetylcholinesterase distribution in the brain of the control participants agreed with the acetylcholinesterase distribution at necropsy. All patients with Alzheimer's disease had multiple cortical regions with a reduced estimated acetylcholinesterase activity in comparison with control participants. The reduction was more pronounced in the parietotemporal cortex, with an average reduction rate of 31% in temporal and 38% in parietal cortex, and less pronounced in other cortical lesions (19% in frontal, 24% in occipital, and 20% in sensorimotor cortex). Each patient was found to have at least two cortical regions with significantly reduced acetylcholinesterase activity. INTERPRETATION: The method we describe for non-invasive in-vivo detection of regional acetylcholinesterase changes in the living human brain that is feasible for biochemical assessment of Alzheimer's disease.
ESTHER : Iyo_1997_Lancet_349_1805
PubMedSearch : Iyo_1997_Lancet_349_1805
PubMedID: 9269216

Title : Brain acetylcholinesterase activity: validation of a PET tracer in a rat model of Alzheimer's disease - Irie_1996_J.Nucl.Med_37_649
Author(s) : Irie T , Fukushi K , Namba H , Iyo M , Tamagami H , Nagatsuka S , Ikota N
Ref : J Nucl Med , 37 :649 , 1996
Abstract : We developed three radioactive acetylcholine analogs--N[14C]methyl-4-piperidyl acetate ([14C]MP4A), propionate ([14C]MP4P) and isobutyrate ([14C]MP4IB)--as radiotracers for measuring brain acetylcholinesterase (AchE) activity in vivo. The principle of our method is that the lipophilic analog diffuses into the brain where it is metabolized by AchE to produce a hydrophilic metabolite, which is trapped at the site of its production. The purpose of this study was to examine whether the tracers would have the sensitivity needed for early diagnosis of Alzheimer' disease using rats with a unilateral lesion in the nucleus basalis magnocellularis (NBM), an animal model of the cholinergic deficit in Alzheimer's disease. METHODS: Rats with a unilateral NBM lesion were prepared, and the N[14C]methyl-4-piperidyl esters and N-Isopropyl-p-[123I]iodoamphetamine([123I]IMP were injected intravenously 30 and 2 min, respectively, before the rats were killed. Uptake of 14C and 123I and AchE activity in the lesioned and unlesioned (control) sides of the cortex were measured simultaneously. RESULTS: The NBM lesion showed reduced cortical AchE activity by 30%-50%, with no side-to-side differences in [123I]MP uptake. Autoradiographic studies showed that uptake of 14C from [14C]MP4A and [14C]MP4P was significantly lower in the lesioned than unlesioned side of the cortex, which agreed well with the AchE histochemical staining patterns. Tissue dissection studies showed different uptake changes for the three compounds when AchE activity in the lesioned side of the cortex was reduced by 50%: 14C uptake from [14C]MP4P, [14C]MP4A and [14C]MP4IB was reduced by 27%, 21% and 7.3%, respectively. Theoretical analysis of the observed sensitivities of the tracers in relation to their in vitro enzymatic properties indicated that tracer sensitivity was highly dependent on the enzymatic hydrolysis rate of the tracer. CONCLUSION: The [14C]MP4A and [14C]MP4P esters had sufficient sensitivity to enable AchE activity changes in the rat cortex of less than 50% to be detected, indicating that the present method is applicable to PET diagnosis of Alzheimer's disease.
ESTHER : Irie_1996_J.Nucl.Med_37_649
PubMedSearch : Irie_1996_J.Nucl.Med_37_649
PubMedID: 8691261

Title : In vivo measurement of acetylcholinesterase activity in the brain with a radioactive acetylcholine analog - Namba_1994_Brain.Res_667_278
Author(s) : Namba H , Irie T , Fukushi K , Iyo M
Ref : Brain Research , 667 :278 , 1994
Abstract : A novel method for visualization of brain acetylcholinesterase (AChE) in vivo has been developed. Following intravenous administration of a radiolabelled acetylcholine analog, N-methyl-3-piperidyl acetate, there was very good agreement between the distribution of radioactivity and AChE activity in the brain of rat and monkey. The method would be applicable for in vivo studies of human brain AChE activity in disorders of central cholinergic systems such as Alzheimer's disease
ESTHER : Namba_1994_Brain.Res_667_278
PubMedSearch : Namba_1994_Brain.Res_667_278
PubMedID: 7697367

Title : Design and evaluation of radioactive acetylcholine analogs for mapping brain acetylcholinesterase (AchE) in vivo - Irie_1994_Nucl.Med.Biol_21_801
Author(s) : Irie T , Fukushi K , Akimoto Y , Tamagami H , Nozaki T
Ref : Nucl Med Biol , 21 :801 , 1994
Abstract : For mapping brain acetylcholinesterase (AchE) in vivo, seven radioactive acetylcholine analogs, N-[14C]methylpiperidyl-3- and 4-acetates, propionates, isobutyrates, and 3-butyrate were newly synthesized and evaluated in mice. The esters readily entered the brain and were hydrolyzed into the hydrophilic metabolite, which was trapped. In brain homogenates, the esters showed a wide range of enzymatic reactivity (about 40-fold), and high specificity for AchE (more than 82%) except the butyrate. Intra-brain distribution of the esters reflected a pattern of AchE activity.
ESTHER : Irie_1994_Nucl.Med.Biol_21_801
PubMedSearch : Irie_1994_Nucl.Med.Biol_21_801
PubMedID: 9234329

Title : Evaluation of phenylmethanesulfonyl fluoride (PMSF) as a tracer candidate mapping acetylcholinesterase in vivo - Irie_1993_Nuc.Med.Biol_20_991
Author(s) : Irie T , Fukushi K , Iyo M
Ref : Nuclear Medicine & Biology , 20 :991 , 1993
Abstract : The availability of phenylmethanesulfonyl fluoride (PMSF), an irreversible cholinesterase inhibitor, for a tracer mapping acetylcholinesterase (AchE) in vivo in brain and other organs was evaluated using [35S]PMSF in mice and rats. [35S]PMSF was well taken up into the brain, heart and muscle, and the radioactivities were trapped in these organs. Pretreatment with non-labeled PMSF decreased 33-40% of the trapped radioactivities in the brain and other organs in mice. However, regional distribution of [35S]PMSF in rat brain did not correlate well with that of AchE activity, suggesting that the selectivity of PMSF toward AchE may be insufficient for use as an in vivo tracer mapping AchE.
ESTHER : Irie_1993_Nuc.Med.Biol_20_991
PubMedSearch : Irie_1993_Nuc.Med.Biol_20_991
PubMedID: 8298579

Title : Determination of basal acetylcholine release in vivo by rat brain dialysis with a U-shaped cannula: effect of SM-10888, a putative therapeutic drug for Alzheimer's disease - Xu_1991_Neurosci.Lett_123_179
Author(s) : Xu M , Nakamura Y , Yamamoto T , Natori K , Irie T , Utsumi H , Kato T
Ref : Neuroscience Letters , 123 :179 , 1991
Abstract : A U-shaped dialysis cannula was implanted into rat frontal cortex, hippocampus and striatum, and after 1 day for surgical recovery the cannula was perfused with Ringer's solution without any acetylcholinesterase (AChE) inhibitor under freely moving conditions. With a highly sensitive assay method for acetylcholine (ACh), the basal ACh content in the dialysates were detectable in those brain regions for several hours. The basal levels in the frontal cortex, hippocampus and striatum were 82 +/- 9, 72 +/- 4, 70 +/- 8 fmol/20 microliters (mean +/- S.E.M.), respectively. When SM-10888, a novel AChE inhibitor and putative therapeutic drug for Alzheimer's disease, was injected intraperitoneally, ACh in the dialysate of the cortex increased in a dose-dependent manner. Changes in the levels of hippocampal and striatal ACh release evoked by SM-10888 were similar to, but smaller than, that in the cortex. These data suggest that since the present assay method is able to determine in vivo basal ACh release in the dialysate without any AChE inhibitor, it is possible to study the effect of a novel drug such as SM-10888 in the brain regions.
ESTHER : Xu_1991_Neurosci.Lett_123_179
PubMedSearch : Xu_1991_Neurosci.Lett_123_179
PubMedID: 2027531

Title : Pharmacological and biochemical assessment of SM-10888, a novel cholinesterase inhibitor - Natori_1990_Jpn.J.Pharmacol_53_145
Author(s) : Natori K , Okazaki Y , Irie T , Katsube J
Ref : Japanese Journal of Pharmacology , 53 :145 , 1990
Abstract : The effects of the compound SM-10888 (9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate) in a number of pharmacological and biochemical tests were studied and compared to those of tacrine (THA), amiridin, HP-029 and physostigmine. SM-10888 inhibited cholinesterase activity (IC50: 2.3 x 10(-7) M) in rat cortical P2 fraction with almost the same potency as THA, while SM-10888 was 2-4 times more potent than amiridin and HP-029, but about 10 times less potent than physostigmine. When given to mice p.o., SM-10888 induced central (hypothermia) and peripheral (salivation) cholinergic effects. When the ratio of the ED50 value for hypothermia to that for salivation was regarded as the index of the selectivity to the central nervous system (CNS), SM-10888 was shown to be about 3 times more selective to the CNS than the other four drugs in mice. The minimum effective dose of SM-10888 for its increasing effect on acetylcholine (ACh) content in the mouse cerebral cortex was about 10 times higher than that of physostigmine, but 5-10 times lower than those of THA, amiridin and HP-029. These results suggest that SM-10888 is an adequate drug for increasing the brain ACh content with less peripheral cholinergic side effects than THA, amiridin, HP-029 and physostigmine.
ESTHER : Natori_1990_Jpn.J.Pharmacol_53_145
PubMedSearch : Natori_1990_Jpn.J.Pharmacol_53_145
PubMedID: 2385001

Title : Effect of a novel CNS-selective cholinesterase inhibitor, SM-10888, on habituation and passive avoidance responses in mice - Okazaki_1990_Jpn.J.Pharmacol_53_211
Author(s) : Okazaki Y , Natori K , Irie T , Katsube J
Ref : Japanese Journal of Pharmacology , 53 :211 , 1990
Abstract : The effects of the tacrine (THA) derivative SM-10888 (9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate) on habituation and passive avoidance responses were studied in mice. We examined its effects on habituation of exploratory activity, measured by photo-cell beam interruptions in a small, simple cage and cycloheximide (CXM)- or electroconvulsive shock (ECS)-induced stepdown type passive avoidance response (PAR) failures in comparison with those of THA, amiridin, HP-029 and physostigmine. SM-10888 (6 mg/kg, p.o.) administered post-acquisition session enhanced the retention of habituation. CXM- and ECS-induced PAR failures were improved by SM-10888 (6 mg/kg, p.o.) administered at pre-training or post-training, respectively. THA enhanced the retention of habituation and improved CXM-induced PAR failure at 30 mg/kg, p.o., but did not affect ECS-induced PAR failure at 1-15 mg/kg, p.o. Amiridin and HP-029 were also effective on habituation and CXM-induced PAR failure at 40-50 mg/kg, p.o., but did not affect ECS-induced PAR failure at the tested doses. Physostigmine showed a moderate improvement only in CXM-induced PAR failure. The results indicate that SM-10888 enhanced habituation and improved PAR failures at much lower doses than THA. This seems to depend on its high selectivity to the central nervous system.
ESTHER : Okazaki_1990_Jpn.J.Pharmacol_53_211
PubMedSearch : Okazaki_1990_Jpn.J.Pharmacol_53_211
PubMedID: 2385006