Computer simulation study on tracer selection problem of reversible and irreversible radioligands for quantitative measurement of enzymes or receptors by PET

第１５回放射性医薬品化学国際シンポジウ

Acetylcholinesterase Imaging: Its Use in Therapy Evaluation and Drug Design

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-[11C]methylaminoacridine or [11C]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 [11C]physostigmine and [11C]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 cerebral pharmacokinetics of such therapeutic drugs.\nAn 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-[11C]methylpiperidine esters. N-[11C]methylpiperidin-4-ylaceta (MP4A) and N-[11C]methylpiperidin-4-yl propionate (MP4P or PMP), have been used for clinical studies of Alzheimer\u27s disease and other neurodegenerative diseases. Both [11C]MP4A-and [11C]MP4P-PET have demonstrated not only the reduction of AChE activity in the cerebral cortex of patients with Alzheimer\u27s disrase (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

Quantification of cerebral enzyme activity with irrevesible radiotracer method: Tracer selection for static image analysis

第6回放射薬剤化学に関する中国／日本合同セミナ

N-Methyl-3-(I-Hydroxy-5-[123I]Iodopent-4-enyl)-4-Acetoxypipe ridine, A Novel Candidate of Acetylcholinesterase Activity Imaging Agent

A novel acetylcholine radioanalog, N-methyl-3-(l-hydroxy-5-[123I]iodopent-4-enyl)-4-acetoxypiperidine, was prepared by radioiodination of the corresponding tributylstannyl precursor that was synthesized in eight steps from 4-piperidone. The tracer has three asymmetric carbons giving eight opical isomers. Two optical isomers were isolated in the precursor synthesis by diastereomeric and enantiomeric separation. In the incubation experiments using rat cerebral homogenate, one optical isomer was hydrolyzed by acetylcholinesterase with high reactivity and selectivity. The tracer is a candidate for mapping cerebral regional acetylcholinesterase activity by single photon emission computed tomography

Brain Acetylcholinesterase Activity in Alzheimer Disease Measure by Positron Emission Tomography

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. Kinetic analysis was performed to calculate k3, an index of acetylcholinesterase activity. The k3 values were significantly reduced in the necortex, hippocampus, and amygdata 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 Alzeimer disease

Non-invasive Measurements of Acetylcholinesterase Activity with Normalized [11C]MP4A-PET Images for Dementia Diagnosis

10th Annual Meeting of the Organization for Human Brain Mappin

Human cerebral acetylcholinesterase activity measured with positron emission tomography: procedure, normal values and effect of age

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 oin 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 hte 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 hte input function. The method should be applicable to patients with Alzheimer\u27s disease and those with other kinds of dementia whose central cholinergic system has been reported to be disturbed