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Imaging of Muscarinic Receptors in the Central Nervous System

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Muscarinic Receptor: From Structure to Animal Models

Part of the book series: Neuromethods ((NM,volume 107))

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Abstract

For the quantitative imaging of muscarinic acetylcholine receptors (mAChR), we developed novel PET probes, (+)N-11C-methyl-3-piperidyl benzilate (11C-(+)3-MPB), and its N-alkyl substitute analogs, and evaluated them in the brains of conscious monkeys (Macaca mulatta) using high-resolution positron emission tomography (PET). Although (+)3-MPB had relatively poor selectivity to the subtypes of mAChR, the regional cortical distribution of 11C-(+)3-MPB was found to be consistent with mAChR density in the living monkey brain as reported in vitro. In contrast, its enantiomeric analog 11C-(−)3-MPB provided homogeneous distribution with no significant specific binding throughout the whole brain. The N-alkyl substitution of alkyl moiety from methyl (11C-(+)3-MPB) to ethyl (11C-(+)3-EPB) and propyl (11C-(+)3-PPB) resulted in lower affinities to mAChR in vitro, the faster kinetics in the living brain, and greater sensitivity to increased endogenous ACh level, induced by acetylcholinesterase (AChE) inhibitor, than 11C-(+)3-MPB. Administration of scopolamine, a mAChR antagonist, reduced 11C-(+)3-MPB binding to mAChR in all regions except the cerebellum, and the reduction of 11C-(+)3-MPB uptake was well correlated with the degree of impairment of working memory performance assessed in conscious monkeys. These results demonstrated that PET imaging with 11C-(+)3-MPB could be useful for diagnosis of neurological diseases associated with impaired mAChR function and cognitive function.

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Author information

Authors and Affiliations

  1. Central Research Laboratory, Hamamatsu Photonics K.K., Hamakita, Hamamatsu, Shizuoka, 434-8601, Japan

    Hideo Tsukada & Shingo Nishiyama

  2. Department of Radiology and Nuclear Medicine, Research Institute of Brain and Blood Vessels-Akita, Akita, Akita, 010-0874, Japan

    Kazuhiro Takahashi

Authors
  1. Hideo Tsukada
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  2. Shingo Nishiyama
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  3. Kazuhiro Takahashi
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Corresponding author

Correspondence to Hideo Tsukada .

Editor information

Editors and Affiliations

  1. Institute of Physiology, Charles University, Prague, Czech Republic

    Jaromir Myslivecek

  2. Department of Neurochemistry, Acad. of Sciences of the Czech Rep. Institute of Physiology, Prague, Czech Republic

    Jan Jakubik

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Tsukada, H., Nishiyama, S., Takahashi, K. (2016). Imaging of Muscarinic Receptors in the Central Nervous System. In: Myslivecek, J., Jakubik, J. (eds) Muscarinic Receptor: From Structure to Animal Models. Neuromethods, vol 107. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2858-3_10

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  • DOI: https://doi.org/10.1007/978-1-4939-2858-3_10

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-2857-6

  • Online ISBN: 978-1-4939-2858-3

  • eBook Packages: Springer Protocols

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