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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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N-[11C]Methylpiperidin-4-yl acetate

[11C]MP4A
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: February 22, 2012.

Chemical name:N-[11C]Methylpiperidin-4-yl acetateimage 11110528 in the ncbi pubchem database
Abbreviated name:[11C]MP4A, [11C]AMP
Synonym:
Agent category:Compound
Target:Acetylcholinesterase (AChE)
Target category:Enzyme
Method of detection:PET
Source of signal:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-Human Primates
  • Checkbox Humans
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Acetylcholine is an endogenous neurotransmitter at cholinergic synapses and neuroneffector junctions in the peripheral and central nervous systems. It acts on nicotinic and muscarinic receptors to mediate complex functions, such as attention, memory, cognition, and consciousness. Degeneration of cholinergic neurons has been observed in several neurodegenerative disease, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), but not in vascular dementia. Acetylcholinesterase (AChE) is the enzyme that terminates cholinergic actions through the rapid hydrolysis of acetylcholine to choline and acetate. AChE is localized on both cholinergic and cholinoceptive neurons in the brain, with the highest activity in the striatum, thalamus, cerebellum, and cerebral cortex (1). AChE has been a target for radioligand development as well as drug development because its levels decrease in AD (1, 2). Radiolabeled AChE inhibitors and acetylcholine analog substrates are the two major approaches to mapping AChE in vivo in the human brain.

For measurements of AChE activity, various labeled esters of 1-methy-4-hydroxypiperidine have been designed and evaluated as acetylcholine substrate analogs (3). One of these analogs, N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A), was chosen for further development as a positron emission tomography (PET) radioligand. It has a tertiary amine structure that makes it lipophilic, and thus it readily crosses the blood-brain barrier (BBB). [11C]MP4A is specifically hydrolyzed by AChE (99% specificity) and yields a hydrophilic metabolite, N-[11C]methylpiperidinol ([11C]MP4OH), which is trapped in the brain because it is too polar to cross the BBB. [11C]MP4A is being developed as a PET agent for the non-invasive study of brain AChE activity in patients with AD and PD.

Synthesis

[PubMed]

Irie et al. (3) reported the synthesis of [14C]MP4A by direct N-methylation of piperidin-4-yl acetate with [14C]methyl iodine in acetone, with a radiochemical yield of 80% (end of synthesis) after purification via high-performance liquid chromatography. Radiochemical purities were >97% with a total synthesis time of ~30 min. Iyo et al. (4) reported a specific activity of 18 GBq/μmol (0.49 Ci/μmol) when they used this same method to prepare [11C]MP4A . Nguyen et al. (5) prepared [11C]MP4A using [11C]methyl triflate for N-methylation in dimethyl sulfoxide, with radiochemical yields of 10-40%. Carpinelli et al. (6) described a fully automated synthesis of [11C]MP4A using [11C]methyl iodine for N-methylation of piperidin-4-yl acetate hydrochloride in anhydrous dimethylformamide; the radiochemical purity of the product was >98%. The radiochemical yields were 20-60% within 40 min after end of bombardment, with an average specific activity of 37 GBq/μmol (1 Ci/μmol) (n = 10).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Irie et al. (7) reported that MP4A was rapidly hydrolyzed to MP4OH and acetic acid by mouse, rat, and human brain homogenates, with 94-99% specificity for AChE. The hydrolysis rate in human cerebral cortex (0.16/fraction/min/g/ml) is about 10% of that in the cerebral cortex of the rat and mouse (1.54/fraction/min/g/ml).

Animal Studies

Rodents

[PubMed]

Biodistribution studies by Irie et al. (7) in mice showed rapid, high accumulation of radioactivity in the brain within minutes after injection of [14C]MP4A. The uptakes in striatum, cortex, and cerebellum were about 10% of injected dose/g at 1 min, and >95% of radioactivity was the hydrolytic metabolite, [14C]MP4OH. There was little difference in regional blood flow measured by [123I]isopropyliodoamphetamine ([123I]IMP). In contrast, [14C]MP4A showed heterogeneous distributions, with striatum/cerebellum and cortex/cerebellum ratios of 2.1-3.8 and 1.4-2.0, respectively.

Kilbourn et al. (8) reported that 30 min after injection in mice, [11C]MP4A showed rapid accumulation in the brain and a regional retention of radioactivity (striatum > cortex, hippocampus > hypothalamus > cerebellum) reflecting known levels of AChE activity in the brain, with >95% of radioactivity in the form of [11C]MP4OH. Striatum/cerebellum and striatum/cortex ratios were 1.94 ± 0.16 and 1.03 ± 0.14, respectively. Retention of radioactivity in all regions was reduced by pretreatment with 3 mg/kg diisopropylfluorophosphate (DFP), a specific irreversible AChE inhibitor. DFP treatment also significantly increased the proportions of intact ester in both the blood and brain.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

Tsukada et al. (9) performed PET studies with [11C]MP4A in 5 young (5.2 ± 1.1 years old) and 5 aged (20.3 ± 2.6 years old) male rhesus monkeys and found rapid accumulation in the brain within minutes after injection. The highest uptake was in the striatum and thalamus, followed by the cerebellum, occipital cortex, temporal cortex, and frontal cortex. Quantitative analysis of [11C]MP4A uptake was usually described by a three-compartment model with three parameters to measure AChE activity (k3) with or without blood sampling. The striatum or cerebellum, used as a “reference region” because of their high AChE activity, reflected a biologic integrator of plasma input function during PET scanning. Donepezil (AChE inhibitor) at doses of 50 and 250 μg/kg suppressed the AChE activity (k3) of [11C]MP4A in all cortical regions in a dose-dependent manner in both age groups. However, the suppression was greater in young than in aged monkeys. AChE inhibition by donepezil led to a dose-dependent increase in acetylcholine levels in the prefrontal cortex of young animals as measured by microdialysis. Aged monkeys showed impaired working memory performance compared with young monkeys, and the impaired performance was partly improved by the administration of donepezil because of facilitation of the cholinergic neuronal system by AChE inhibition.

Human Studies

[PubMed]

Kinetic analysis of [11C]MP4A for measurement of cerebral AChE activity can be performed with or without arterial blood sampling (10-13). A three-compartment model with three parameters is used to measure AChE hydrolysis of the tracer (k3), the transport rate constant of the tracer from blood to brain through the BBB (K1), and the transport rate constant of the tracer from brain to blood through the BBB (k2). Using [11C]MP4A PET, Iyo et al. (4) studied eight elderly healthy controls and five patients with AD who had mild dementia. The estimated AChE distribution in the brain of the control subjects agreed with the AChE distribution at biopsy. The median K1 and k2 values for all regions in the controls were 0.54 ± 0.10 ml/g/min and 0.13 ± 0.02/min, respectively. The median K1 and k2 values in the AD patients were 0.42 ± 0.07ml/g/min and 0.11 ± 0.02/min, respectively. This reduction is attributable to the cortical reduction of regional blood flow in the AD patients as measured by [123I]IMP. All patients with AD had multiple cortical regions with a reduced k3 value compared with controls. The reduction in k3 was heterogeneous both regionally and individually. The reduction was more marked in the temporoparietal cortex, with an average reduction rate of 31% in the temporal and 38% in the parietal cortex, with less pronounced reductions in other cortical lesions (19% in the frontal, 24% in the occipital, and 20% in the sensorimotor cortex). Each patient was found to have at least two cortical regions with significantly reduced AChE activity.

Shinotoh et al. (14) subsequently confirmed a significant reduction in k3 values in the neocortex, hippocampus, and amygdale in 15 early-onset AD patients, whereas k3 values were significantly reduced only in the temporoparietal cortex and amygdale in late-onset AD patients. There was a significant correlation between the cortical k3 values and the Mini-Mental State Examination scores. Herholz et al. (15) found that AChE activity was significantly reduced in the amygdale and cerebral cortex in patients with mild to moderate AD, whereas reduction of cerebral blood flow and glucose metabolism was more limited to temporoparietal regions. Rinne et al. (16) cautioned that the k3 values in the hippocampus were only slightly reduced in mild cognitive impairment and early AD compared with AD, limiting their usefulness in detecting early AD.

Hilker et al. (17) performed combined PET with [11C]MP4A and [18F]fluorodopa (FDOPA) for evaluation of cholinergic and dopaminergic transmitter changes in 17 non-demented patients with PD and 10 PD patients with associated dementia (PDD) compared with 31 age-matched controls. The striatal FDOPA uptake was significantly decreased in PD and PDD without differences between the groups. The global cortical k3 values for [11C]MP4A were strongly reduced in PDD (29.7%; P < 0.001) and moderately decreased in PD (10.7%; P < 0.01) compared with controls. The PDD group had lower parietal k3 values for [11C]MP4A than did patients with PD. Frontal and temporoparietal cortices showed a significant correlation of striatal FDOPA reduction and decreased k3 for [11C]MP4A in patients with PDD.

Internal dosimetry data for [11C]MP4A in humans have not yet been available in the literature.

References

1.
Shinotoh H., Fukushi K., Nagatsuka S., Irie T. Acetylcholinesterase imaging: its use in therapy evaluation and drug design. Curr Pharm Des. 2004;10(13):1505–17. [PubMed: 15134572]
2.
Herholz K. PET studies in dementia. Ann Nucl Med. 2003;17(2):79–89. [PubMed: 12790355]
3.
Irie T., Fukushi K., Akimoto Y., Tamagami H., Nozaki T. Design and evaluation of radioactive acetylcholine analogs for mapping brain acetylcholinesterase (AchE) in vivo. Nucl Med Biol. 1994;21(6):801–8. [PubMed: 9234329]
4.
Iyo M., Namba H., Fukushi K., Shinotoh H., Nagatsuka S., Suhara T., Sudo Y., Suzuki K., Irie T. Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer's disease. Lancet. 1997;349(9068):1805–9. [PubMed: 9269216]
5.
Nguyen T.B., Snyder S.E., Kilbourn M.R. Syntheses of carbon-11 labeled piperidine esters as potential in vivo substrates for acetylcholinesterase. Nucl Med Biol. 1998;25(8):761–8. [PubMed: 9863564]
6.
Carpinelli A., Magni F., Cattaneo A., Matarrese M., Turolla E., Todde S., Bosso N., Galli Kienle M., Fazio F. Improved synthesis and radiolabeling of [11C]MP4A, a suitable ligand for the investigation of the cholinergic system using PET. Appl Radiat Isot. 2006;64(2):182–6. [PubMed: 16169239]
7.
Irie T., Fukushi K., Namba H., Iyo M., Tamagami H., Nagatsuka S., Ikota N. Brain acetylcholinesterase activity: validation of a PET tracer in a rat model of Alzheimer's disease. J Nucl Med. 1996;37(4):649–55. [PubMed: 8691261]
8.
Kilbourn M.R., Nguyen T.B., Snyder S.E., Sherman P. N-[11C]methylpiperidine esters as acetylcholinesterase substrates: an in vivo structure-reactivity study. Nucl Med Biol. 1998;25(8):755–60. [PubMed: 9863563]
9.
Tsukada H., Nishiyama S., Fukumoto D., Ohba H., Sato K., Kakiuchi T. Effects of acute acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function: Functional imaging of the conscious monkey brain using animal PET in combination with microdialysis. Synapse. 2004;52(1):1–10. [PubMed: 14755627]
10.
Herholz K., Lercher M., Wienhard K., Bauer B., Lenz O., Heiss W.D. PET measurement of cerebral acetylcholine esterase activity without blood sampling. Eur J Nucl Med. 2001;28(4):472–7. [PubMed: 11357497]
11.
Nagatsuka Si S., Fukushi K., Shinotoh H., Namba H., Iyo M., Tanaka N., Aotsuka A., Ota T., Tanada S., Irie T. 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. J Cereb Blood Flow Metab. 2001;21(11):1354–66. [PubMed: 11702050]
12.
Namba H., Fukushi K., Nagatsuka S., Iyo M., Shinotoh H., Tanada S., Irie T. Positron emission tomography: quantitative measurement of brain acetylcholinesterase activity using radiolabeled substrates. Methods. 2002;27(3):242–50. [PubMed: 12183113]
13.
Tanaka N., Fukushi K., Shinotoh H., Nagatsuka S., Namba H., Iyo M., Aotsuka A., Ota T., Tanada S., Irie T. 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. J Cereb Blood Flow Metab. 2001;21(3):295–306. [PubMed: 11295884]
14.
Shinotoh H., Namba H., Fukushi K., Nagatsuka S., Tanaka N., Aotsuka A., Ota T., Tanada S., Irie T. Progressive loss of cortical acetylcholinesterase activity in association with cognitive decline in Alzheimer's disease: a positron emission tomography study. Ann Neurol. 2000;48(2):194–200. [PubMed: 10939570]
15.
Herholz K., Weisenbach S., Zundorf G., Lenz O., Schroder H., Bauer B., Kalbe E., Heiss W.D. In vivo study of acetylcholine esterase in basal forebrain, amygdala, and cortex in mild to moderate Alzheimer disease. Neuroimage. 2004;21(1):136–43. [PubMed: 14741650]
16.
Rinne J.O., Kaasinen V., Jarvenpaa T., Nagren K., Roivainen A., Yu M., Oikonen V., Kurki T. Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2003;74(1):113–5. [PMC free article: PMC1738186] [PubMed: 12486280]
17.
Hilker R., Thomas A.V., Klein J.C., Weisenbach S., Kalbe E., Burghaus L., Jacobs A.H., Herholz K., Heiss W.D. Dementia in Parkinson disease: functional imaging of cholinergic and dopaminergic pathways. Neurology. 2005;65(11):1716–22. [PubMed: 16344512]
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