Kikuchi T

References (20)

Title : Improved identification of tumors in 18F-FDG-PET examination by normalizing the standard uptake in the liver based on blood test data - Alam_2024_Int.J.Comput.Assist.Radiol.Surg__
Author(s) : Alam MA , Hanaoka S , Nomura Y , Kikuchi T , Nakao T , Takenaga T , Hayashi N , Yoshikawa T , Abe O
Ref : Int J Comput Assist Radiol Surg , : , 2024
Abstract : PURPOSE: Standardized uptake values (SUVs) derived from (18)F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography are a crucial parameter for identifying tumors or abnormalities in an organ. Moreover, exploring ways to improve the identification of tumors or abnormalities using a statistical measurement tool is important in clinical research. Therefore, we developed a fully automatic method to create a personally normalized Z-score map of the liver SUV. METHODS: The normalized Z-score map for each patient was created using the SUV mean and standard deviation estimated from blood-test-derived variables, such as alanine aminotransferase and aspartate aminotransferase, as well as other demographic information. This was performed using the least absolute shrinkage and selection operator (LASSO)-based estimation formula. We also used receiver operating characteristic (ROC) to analyze the results of people with and without hepatic tumors and compared them to the ROC curve of normal SUV. RESULTS: A total of 7757 people were selected for this study. Of these, 7744 were healthy, while 13 had abnormalities. The area under the ROC curve results indicated that the anomaly detection approach (0.91) outperformed only the maximum SUV (0.89). To build the LASSO regression, sets of covariates, including sex, weight, body mass index, blood glucose level, triglyceride, total cholesterol, gamma-glutamyl transpeptidase, total protein, creatinine, insulin, albumin, and cholinesterase, were used to determine the SUV mean, whereas weight was used to determine the SUV standard deviation. CONCLUSION: The Z-score normalizes the mean and standard deviation. It is effective in ROC curve analysis and increases the clarity of the abnormality. This normalization is a key technique for effective measurement of maximum glucose consumption by tumors in the liver.
ESTHER : Alam_2024_Int.J.Comput.Assist.Radiol.Surg__
PubMedSearch : Alam_2024_Int.J.Comput.Assist.Radiol.Surg__
PubMedID: 38180621

Title : Comparative and population genomic landscape of Phellinus noxius: A hypervariable fungus causing root rot in trees - Chung_2017_Mol.Ecol_26_6301
Author(s) : Chung CL , Lee TJ , Akiba M , Lee HH , Kuo TH , Liu D , Ke HM , Yokoi T , Roa MB , Lu MJ , Chang YY , Ann PJ , Tsai JN , Chen CY , Tzean SS , Ota Y , Hattori T , Sahashi N , Liou RF , Kikuchi T , Tsai IJ
Ref : Mol Ecol , 26 :6301 , 2017
Abstract : The order Hymenochaetales of white rot fungi contain some of the most aggressive wood decayers causing tree deaths around the world. Despite their ecological importance and the impact of diseases they cause, little is known about the evolution and transmission patterns of these pathogens. Here, we sequenced and undertook comparative genomic analyses of Hymenochaetales genomes using brown root rot fungus Phellinus noxius, wood-decomposing fungus Phellinus lamaensis, laminated root rot fungus Phellinus sulphurascens and trunk pathogen Porodaedalea pini. Many gene families of lignin-degrading enzymes were identified from these fungi, reflecting their ability as white rot fungi. Comparing against distant fungi highlighted the expansion of 1,3-beta-glucan synthases in P. noxius, which may account for its fast-growing attribute. We identified 13 linkage groups conserved within Agaricomycetes, suggesting the evolution of stable karyotypes. We determined that P. noxius has a bipolar heterothallic mating system, with unusual highly expanded ~60 kb A locus as a result of accumulating gene transposition. We investigated the population genomics of 60 P. noxius isolates across multiple islands of the Asia Pacific region. Whole-genome sequencing showed this multinucleate species contains abundant poly-allelic single nucleotide polymorphisms with atypical allele frequencies. Different patterns of intra-isolate polymorphism reflect mono-/heterokaryotic states which are both prevalent in nature. We have shown two genetically separated lineages with one spanning across many islands despite the geographical barriers. Both populations possess extraordinary genetic diversity and show contrasting evolutionary scenarios. These results provide a framework to further investigate the genetic basis underlying the fitness and virulence of white rot fungi.
ESTHER : Chung_2017_Mol.Ecol_26_6301
PubMedSearch : Chung_2017_Mol.Ecol_26_6301
PubMedID: 28926153
Gene_locus related to this paper: 9homo-a0a286uk81

Title : The genomic basis of parasitism in the Strongyloides clade of nematodes - Hunt_2016_Nat.Genet_48_299
Author(s) : Hunt VL , Tsai IJ , Coghlan A , Reid AJ , Holroyd N , Foth BJ , Tracey A , Cotton JA , Stanley EJ , Beasley H , Bennett HM , Brooks K , Harsha B , Kajitani R , Kulkarni A , Harbecke D , Nagayasu E , Nichol S , Ogura Y , Quail MA , Randle N , Xia D , Brattig NW , Soblik H , Ribeiro DM , Sanchez-Flores A , Hayashi T , Itoh T , Denver DR , Grant W , Stoltzfus JD , Lok JB , Murayama H , Wastling J , Streit A , Kikuchi T , Viney M , Berriman M
Ref : Nat Genet , 48 :299 , 2016
Abstract : Soil-transmitted nematodes, including the Strongyloides genus, cause one of the most prevalent neglected tropical diseases. Here we compare the genomes of four Strongyloides species, including the human pathogen Strongyloides stercoralis, and their close relatives that are facultatively parasitic (Parastrongyloides trichosuri) and free-living (Rhabditophanes sp. KR3021). A significant paralogous expansion of key gene families-families encoding astacin-like and SCP/TAPS proteins-is associated with the evolution of parasitism in this clade. Exploiting the unique Strongyloides life cycle, we compare the transcriptomes of the parasitic and free-living stages and find that these same gene families are upregulated in the parasitic stages, underscoring their role in nematode parasitism.
ESTHER : Hunt_2016_Nat.Genet_48_299
PubMedSearch : Hunt_2016_Nat.Genet_48_299
PubMedID: 26829753
Gene_locus related to this paper: 9bila-a0a1i8c9u2 , 9bila-a0a1i8cf76 , 9bila-a0a1i8d2w3 , 9bila-a0a1i8ce18 , 9bila-a0a1i8cmc7

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 : The genome and transcriptome of Haemonchus contortus, a key model parasite for drug and vaccine discovery - Laing_2013_Genome.Biol_14_R88
Author(s) : Laing R , Kikuchi T , Martinelli A , Tsai IJ , Beech RN , Redman E , Holroyd N , Bartley DJ , Beasley H , Britton C , Curran D , Devaney E , Gilabert A , Hunt M , Jackson F , Johnston SL , Kryukov I , Li K , Morrison AA , Reid AJ , Sargison N , Saunders GI , Wasmuth JD , Wolstenholme A , Berriman M , Gilleard JS , Cotton JA
Ref : Genome Biol , 14 :R88 , 2013
Abstract : BACKGROUND: The small ruminant parasite Haemonchus contortus is the most widely used parasitic nematode in drug discovery, vaccine development and anthelmintic resistance research. Its remarkable propensity to develop resistance threatens the viability of the sheep industry in many regions of the world and provides a cautionary example of the effect of mass drug administration to control parasitic nematodes. Its phylogenetic position makes it particularly well placed for comparison with the free-living nematode Caenorhabditis elegans and the most economically important parasites of livestock and humans.
RESULTS: Here we report the detailed analysis of a draft genome assembly and extensive transcriptomic dataset for H. contortus. This represents the first genome to be published for a strongylid nematode and the most extensive transcriptomic dataset for any parasitic nematode reported to date. We show a general pattern of conservation of genome structure and gene content between H. contortus and C. elegans, but also a dramatic expansion of important parasite gene families. We identify genes involved in parasite-specific pathways such as blood feeding, neurological function, and drug metabolism. In particular, we describe complete gene repertoires for known drug target families, providing the most comprehensive understanding yet of the action of several important anthelmintics. Also, we identify a set of genes enriched in the parasitic stages of the lifecycle and the parasite gut that provide a rich source of vaccine and drug target candidates.
CONCLUSIONS: The H. contortus genome and transcriptome provide an essential platform for postgenomic research in this and other important strongylid parasites.
ESTHER : Laing_2013_Genome.Biol_14_R88
PubMedSearch : Laing_2013_Genome.Biol_14_R88
PubMedID: 23985316
Gene_locus related to this paper: haeco-u6nsf0 , haeco-u6psa2 , haeco-u6pu58

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 : Genomic insights into the origin of parasitism in the emerging plant pathogen Bursaphelenchus xylophilus - Kikuchi_2011_PLoS.Pathog_7_e1002219
Author(s) : Kikuchi T , Cotton JA , Dalzell JJ , Hasegawa K , Kanzaki N , McVeigh P , Takanashi T , Tsai IJ , Assefa SA , Cock PJ , Otto TD , Hunt M , Reid AJ , Sanchez-Flores A , Tsuchihara K , Yokoi T , Larsson MC , Miwa J , Maule AG , Sahashi N , Jones JT , Berriman M
Ref : PLoS Pathog , 7 :e1002219 , 2011
Abstract : Bursaphelenchus xylophilus is the nematode responsible for a devastating epidemic of pine wilt disease in Asia and Europe, and represents a recent, independent origin of plant parasitism in nematodes, ecologically and taxonomically distinct from other nematodes for which genomic data is available. As well as being an important pathogen, the B. xylophilus genome thus provides a unique opportunity to study the evolution and mechanism of plant parasitism. Here, we present a high-quality draft genome sequence from an inbred line of B. xylophilus, and use this to investigate the biological basis of its complex ecology which combines fungal feeding, plant parasitic and insect-associated stages. We focus particularly on putative parasitism genes as well as those linked to other key biological processes and demonstrate that B. xylophilus is well endowed with RNA interference effectors, peptidergic neurotransmitters (including the first description of ins genes in a parasite) stress response and developmental genes and has a contracted set of chemosensory receptors. B. xylophilus has the largest number of digestive proteases known for any nematode and displays expanded families of lysosome pathway genes, ABC transporters and cytochrome P450 pathway genes. This expansion in digestive and detoxification proteins may reflect the unusual diversity in foods it exploits and environments it encounters during its life cycle. In addition, B. xylophilus possesses a unique complement of plant cell wall modifying proteins acquired by horizontal gene transfer, underscoring the impact of this process on the evolution of plant parasitism by nematodes. Together with the lack of proteins homologous to effectors from other plant parasitic nematodes, this confirms the distinctive molecular basis of plant parasitism in the Bursaphelenchus lineage. The genome sequence of B. xylophilus adds to the diversity of genomic data for nematodes, and will be an important resource in understanding the biology of this unusual parasite.
ESTHER : Kikuchi_2011_PLoS.Pathog_7_e1002219
PubMedSearch : Kikuchi_2011_PLoS.Pathog_7_e1002219
PubMedID: 21909270
Gene_locus related to this paper: burxy-a0a1i7rsb1

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 : 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 : 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 : 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 : 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 : 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 : Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile - Hirose_2004_J.Psychopharmacol_18_375
Author(s) : Hirose T , Uwahodo Y , Yamada S , Miwa T , Kikuchi T , Kitagawa H , Burris KD , Altar CA , Nabeshima T
Ref : J Psychopharmacol , 18 :375 , 2004
Abstract : The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum prolactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated using several pharmaco-behavioural test systems in mice and rats, both in vivo and ex vivo, and compared with those of other conventional and atypical antipsychotics. Each of the antipsychotics induced catalepsy and inhibited apomorphine-induced stereotypy. The catalepsy liability ratios for these drugs were 6.5 for aripiprazole, 4.7 for both olanzapine and risperidone. The ptosis liability ratios for aripiprazole, olanzapine and risperidone were 14, 7.2 and 3.3, respectively. Aripiprazole slightly increased DOPA accumulation in the forebrain of reserpinised mice, reduced 5-HTP accumulation at the highest dose and exhibited a weaker inhibition of 5-methoxy-N,N-dimethyl-tryptamine-induced head twitches. Aripiprazole did not inhibit physostigmine- or norepinephrine-induced lethality in rats. In conclusion, aripiprazole shows a favourable preclinical efficacy and side-effect profile compared to a typical antipsychotics. This profile may result from its high affinity partial agonist activity at D2 and 5-HT1A receptors and its antagonism of 5-HT2A receptors.
ESTHER : Hirose_2004_J.Psychopharmacol_18_375
PubMedSearch : Hirose_2004_J.Psychopharmacol_18_375
PubMedID: 15358981

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 : Attenuation of scopolamine-induced and age-associated memory impairments by the sigma and 5-hydroxytryptamine(1A) receptor agonist OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quino linone monomethanesulfonate) - Tottori_2002_J.Pharmacol.Exp.Ther_301_249
Author(s) : Tottori K , Nakai M , Uwahodo Y , Miwa T , Yamada S , Oshiro Y , Kikuchi T , Altar CA
Ref : Journal of Pharmacology & Experimental Therapeutics , 301 :249 , 2002
Abstract : Sigma and 5-HT(1A) receptor stimulation can increase acetylcholine (ACh) release in the brain. Because ACh release facilitates learning and memory, we evaluated the degree to which OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quino linone monomethane sulfonate), a novel sigma and 5-HT(1A) receptor agonist, can augment ACh release and improve learning impairments in rats due to cholinergic- or age-related deficits. Single oral administration of OPC-14523 improved scopolamine-induced learning impairments in the passive-avoidance task and memory impairment in the Morris water maze. The chronic oral administration of OPC-14523 attenuated age-associated impairments of learning acquisition in the water maze and in the conditioned active-avoidance response test. OPC-14523 did not alter basal locomotion or inhibit acetylcholinesterase (AChE) activity at concentrations up to 100 microM and, unlike AChE inhibitors, did not cause peripheral cholinomimetic responses. ACh release in the dorsal hippocampus of freely moving rats increased after oral delivery of OPC-14523 and after local delivery of OPC-14523 into the hippocampus. The increases in hippocampal ACh release were blocked by the sigma receptor antagonist NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine). Thus, OPC-14523 improves scopolamine-induced and age-associated learning and memory impairments by enhancing ACh release, due to a stimulation of sigma and probably 5-HT(1A) receptors. Combined sigma/5-HT(1A) receptor agonism may be a novel approach to ameliorate cognitive disorders associated with age-associated cholinergic deficits.
ESTHER : Tottori_2002_J.Pharmacol.Exp.Ther_301_249
PubMedSearch : Tottori_2002_J.Pharmacol.Exp.Ther_301_249
PubMedID: 11907181

Title : Progressive degeneration of motor nerve terminals in GAD mutant mouse with hereditary sensory axonopathy - Miura_1993_Neuropathol.Appl.Neurobiol_19_41
Author(s) : Miura H , Oda K , Endo C , Yamazaki K , Shibasaki H , Kikuchi T
Ref : Neuropathol Appl Neurobiol , 19 :41 , 1993
Abstract : The evolution of motor nerve degeneration was examined in gracile axonal dystrophy (GAD) mutant mice, which develop initial sensory ataxia and subsequent motor paresis. Using the anterior gracilis (AG) muscle, which is innervated at two discrete and well-separated endplate zones, we demonstrated that axonal degeneration occurred first at motor nerve terminals in the distal endplate zone, and then extended gradually from the distal to the more proximal parts of affected axons in the intra-muscular nerve trunk. In contrast to the degeneration in the distal zone, active degeneration was less marked in the proximal endplate zone and, furthermore, most terminal axons had begun to produce regenerating sprouts. Ventral horn cells were histologically normal, even at advanced stages. These results indicate that, as previously observed in sensory nerves, dying back degeneration progresses later in the lower motor neuron system, even within one muscle. The mechanism(s) influencing the activation of axonal regeneration are discussed. This mutant mouse will be a useful model for the study of regenerating phenomena in dying back degeneration of genetically compromised motor neurons, as well as for the study of the pathogenesis of hereditary sensory and motor neuropathies in man.
ESTHER : Miura_1993_Neuropathol.Appl.Neurobiol_19_41
PubMedSearch : Miura_1993_Neuropathol.Appl.Neurobiol_19_41
PubMedID: 8474599