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Dose-dependent sigma-1 receptor occupancy by donepezil in rat brain can be assessed with 11C-SA4503 and microPET

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An Erratum to this article was published on 08 April 2014

Abstract

Rationale

Sigma-1 receptor agonists are under investigation as potential disease-modifying agents for several CNS disorders. Donepezil, an acetylcholinesterase inhibitor used for the symptomatic treatment of Alzheimer’s disease, is also a high-affinity sigma-1 agonist.

Objectives

The objectives of the present study were to investigate if the sigma-1 agonist tracer 11C-SA4503 and microPET can be used to determine sigma-1 receptor occupancy (RO) of donepezil in the rat brain; to establish RO of donepezil at doses commonly used in rodent behavioural studies; and to determine the effective plasma concentration of donepezil required for 50 % of max-min occupancy (EC50).

Methods

Male Wistar rats were pre-treated with donepezil (0.1 to 10 mg/kg) for about 1 h before microPET scans using 11C-SA4503. The total distribution volume (V T) of the tracer was determined by Logan graphical analysis using time activity curves from arterial plasma and regions of interest drawn around the entire brain and individual brain regions. RO by donepezil was calculated from a modified Lassen plot, and ED50 was estimated from the sigmoidal dose-response curves obtained when the RO was plotted against log donepezil dose.

Results

A dose-dependent reduction was observed for V T in the whole brain as well as individual brain regions. RO increased dose-dependently and was 93 % at 10 mg/kg. ED50 was 1.29 mg/kg.

Conclusions

Donepezil, in the common dose range, was found to dose-dependently occupy a significant fraction of the sigma-1 receptor population. The data indicate that it is possible to determine sigma-1 RO by an agonist drug in rat brain, using 11C-SA4503 and microPET.

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Acknowledgments

We would like to thank Chantal Kwizera for the tracer synthesis and Jurgen WA Sijbesma, Mohammed Khayum, Siddesh Hartimath, Soumen Paul, Vladimir Shalgunov and Willem Jan Kuik for the assistance during the scanning procedure. This study was supported by University funding (bursary stipend to NKR).

Conflict of interest

There are no circumstances that could be perceived as a potential conflict of interest.

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Authors and Affiliations

  1. Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands

    Nisha K. Ramakrishnan, Anniek K. D. Visser, Marianne Schepers, Gert Luurtsema, Philip H. Elsinga, Rudi A. J. O. Dierckx & Aren van Waarde

  2. Brain Physiology Research Unit, Semmelweis University, Budapest, Hungary

    Csaba J. Nyakas

  3. Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

    Kiichi Ishiwata

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  1. Nisha K. Ramakrishnan
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  2. Anniek K. D. Visser
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  8. Rudi A. J. O. Dierckx
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  9. Aren van Waarde
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Correspondence to Aren van Waarde.

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Ramakrishnan, N.K., Visser, A.K.D., Schepers, M. et al. Dose-dependent sigma-1 receptor occupancy by donepezil in rat brain can be assessed with 11C-SA4503 and microPET. Psychopharmacology 231, 3997–4006 (2014). https://doi.org/10.1007/s00213-014-3533-2

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  • DOI: https://doi.org/10.1007/s00213-014-3533-2

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