Design and evaluation of radioactive acetylcholine analogs for mapping brain acetylcholinesterase (AchE) in vivo

Irie, Toshiaki; Fukushi, Kiyoshi; Akimoto, Yoshio; Tamagami, Hiroshi; Nozaki, Tadashi

doi:10.1016/0969-8051(94)90159-7

Cited by 112 publications

(75 citation statements)

References 12 publications

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“…12 The hydrolyzed radioligand becomes trapped as a hydrophilic product locally in the brain following the AChE biodistribution. AChE has been recognized since 1966 as a reliable marker for brain cholinergic pathways including in the human brain.…”

Section: Ache Pet Imaging the [mentioning

confidence: 99%

Age-associated leukoaraiosis and cortical cholinergic deafferentation

Bohnen¹,

Müller²,

Kuwabara³

et al. 2009

Neurology

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Section: Ache Pet Imaging the [mentioning

confidence: 99%

Age-associated leukoaraiosis and cortical cholinergic deafferentation

Bohnen¹,

Müller²,

Kuwabara³

et al. 2009

Neurology

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“…In recent years, N-[ 11 C]methylpiperidin-4-yl acetate ([ 11 C]MP4A) (Irie et al, 1994) and N-[ 11 C]methylpiperidin-4-yl propionate ([ 11 C]MP4P) (Irie et al, 1994;Kilbourn et al, 1996) have been developed as radiotracers for brain AChE mapping and applied to quantification of neocortical AChE activity in healthy subjects (Namba et al, 1999;Koeppe et al, 1999) and in patients with AD (Iyo et al, 1997;Kuhl et al, 1999). Both tracers were also applied to evaluating the inhibitory effect of donepezil on brain AChE activity in AD patients (Kuhl et al, 2000;Shinotoh et al, 2001;Kaasinen et al, 2002) and in monkeys (Tsukada et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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

Kikuchi

Fukushi

et al. 2005

Neuropsychopharmacol

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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 mg/kg (donepezil-1; N ¼ 5) or 250 mg/kg (donepezil-2; N ¼ 5), were performed using the same monkeys at 4-week intervals. Before each PET scan, baseline PET scans (N ¼ 10 in total) were performed without donepezil. The plasma donepezil concentrations 14 min after intravenous injection were proportional to the doses, 17.272.9 ng/ml (donepezil-1) and 44.075.0 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 (estimate7SE) were 4279.0 (ng/ml; donepezil-1), 3473.2 (donepezil-2), and 3774.1 (combined data). The present method may be useful for in vivo evaluation of other AChE inhibitors and novel drugs.

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“…Previous work identified several potential PET tra cers for quantification of AChE activity including N-e IC]methylpiperidin-4-yl acetate (MP4A or AMP), N-e IC]methylpiperidin-4-yl propionate (MP4P or PMP), and N- [IIC]methylpiperidin-4-yl isobutyrate (MPIB or iBMP) Irie et al (1994) conclude that [11C]MP4A (AMP) and [11C]MP4P (PMP) were the two most promising tracers of those tested and selected e IC]MP4A as the tracer to pursue for human studies (Iyo et aI., 1997;Namba et aI., 1998) because of its higher specificity for AChE relative to butyrylcholines terase. However, along with its higher specificity for AChE, [ 1 l C]MP4A has a higher hydrolysis rate.…”

Section: Kinetic Analysis Of R L Fc]pmp Li5imentioning

confidence: 99%

Kinetic Modeling of N-[¹¹C]Methylpiperidin-4-yl Propionate: Alternatives for Analysis of an Irreversible Positron Emission Tomography Tracer for Measurement of Acetylcholinesterase Activity in Human Brain

Koeppe

Frey

Snyder

et al. 1999

J Cereb Blood Flow Metab

102

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Summary: N-[IIC]Methylpiperidin-4-yl propionate(C I ClPMP) is a substrate for hydrolysis by acetylcholinester ase (AChE) . This work evaluates kinetic analysis alternatives for estimation of relative AChE activity using dynamic positron emission tomography (PET) studies of rIIC]PMP. The PET studies were performed on three groups of subjects: (I) 12 normal volunteer subjects, aged 20 to 45 years, who received a single intravenbus injection of 16 to 32 mCi of C I ClPMP; (2) six subjects, aged 21 to 44 years, who received two 16-mCi injections of C IC]PMP (baseline and visual stimulation, re spectively); and (3) five subjects, aged 24 to 40 years, who received two 16-mCi injections separated by 200 minutes (baseline and after a I-hour constant infusion of 1.5 mg of physostigmine, respectively) . Dynamic acquisition consisted of a 17-frame sequence over 80 minutes. All analysis methods were based on a first-order kinetic model consisting of two tissue compartments with the parameter k3' representing PMP hydrolysis, being the index of AChE activity. Four different schemes were used to estimate k3: (1) an unconstrained non linear least-squares fit estimating blood-brain barrier transport Positron emission tomography (PET) offers the ability to quantify biochemical features in living humans through the use of radiolabeled tracers and the applica tion of tracer kinetics and compartmental analysis. This study evaluates kinetic analysis alternatives for charac- 1150parameters, K I and k2' in addition to the hydrolysis rate con stant k3; (2) and (3) , two methods of constraining the fit by fixing the volume of distribution of free tracer (DVfree); and (4), a direct estimation of k3 without use of an arterial input function based on the shape of the tissue time-activity curve alone. Results showed that k3 values from the unconstrained fitting and no input methods were estimated with similar ac curacy, whereas the two methods using DVfrce constraints yielded similar results. The authors conclude that the optimal analysis method for C iClPMP differs as a function of AChE activity. All four methods gave precise measures of k3 in re gions with low AChE activity (-10% coefficient of variation in cortex), but surprisingly, with unconstrained methods yielding estimates with lower variability than constrained methods. In regions with moderate to high AChE activity, constrained methods were required to yield meaningful estimates and were superior to the unconstrained methods. Key Words:N-C I Clmethylpiperidin-4-yl propionate-Tracer kinetics Acetylcholinesterase-Positron emission tomography.terizing the in vivo behavior of N-e l C]methylpiperidin-4-yl propionate (C l C]PMP) to yield quantitative esti mates of the model parameter k3 as an index of regional acetylcholinesterase (AChE) activity in the human brain. Acetylcholine, the acetic acid ester of choline, is a neu rotransmitter present in cholinergic synapses of the CNS. Acetylcholinesterase is an enzyme of the CNS (as well as muscles and red cells) that catalyzes the hydrolysis...

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Design and evaluation of radioactive acetylcholine analogs for mapping brain acetylcholinesterase (AchE) in vivo

Cited by 112 publications

References 12 publications

Age-associated leukoaraiosis and cortical cholinergic deafferentation

Age-associated leukoaraiosis and cortical cholinergic deafferentation

Estimation of Plasma IC50 of Donepezil Hydrochloride for Brain Acetylcholinesterase Inhibition in Monkey Using N-[11C]methylpiperidin-4-yl Acetate ([11C]MP4A) and PET

Kinetic Modeling of N-[¹¹C]Methylpiperidin-4-yl Propionate: Alternatives for Analysis of an Irreversible Positron Emission Tomography Tracer for Measurement of Acetylcholinesterase Activity in Human Brain

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Design and evaluation of radioactive acetylcholine analogs for mapping brain acetylcholinesterase (AchE) in vivo

Cited by 112 publications

References 12 publications

Age-associated leukoaraiosis and cortical cholinergic deafferentation

Age-associated leukoaraiosis and cortical cholinergic deafferentation

Estimation of Plasma IC50 of Donepezil Hydrochloride for Brain Acetylcholinesterase Inhibition in Monkey Using N-[11C]methylpiperidin-4-yl Acetate ([11C]MP4A) and PET

Kinetic Modeling of N-[11C]Methylpiperidin-4-yl Propionate: Alternatives for Analysis of an Irreversible Positron Emission Tomography Tracer for Measurement of Acetylcholinesterase Activity in Human Brain

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Kinetic Modeling of N-[¹¹C]Methylpiperidin-4-yl Propionate: Alternatives for Analysis of an Irreversible Positron Emission Tomography Tracer for Measurement of Acetylcholinesterase Activity in Human Brain