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Preclinical and the first clinical studies on [11C]CHIBA-1001 for mapping α7 nicotinic receptors by positron emission tomography

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Abstract

Objective

4-[11C]methylphenyl 2,5-diazabicyclo[3.2.2]nonane-2-carboxylate ([11C]CHIBA-1001), a 4-methyl-substituted derivative of the selective α7 nicotinic acetylcholine receptor (α7 nAChR) partial agonist 4-bromophenyl 1,4 diazabicyclo[3.2.2]nonane-4-carboxylate (SSR180711), is a potential radioligand for mapping α7 nAChRs in the brain by positron emission tomography (PET). In this study, we performed preclinical and first clinical PET studies using [11C]CHIBA-1001 for imaging α7 nAChRs in the human brain.

Methods

[11C]CHIBA-1001 was synthesized by methylation of the tributylstannyl precursor with [11C]CH3I in a palladium-promoted Stille cross-coupling reaction. The radiation absorbed-dose of [11C]CHIBA-1001 in humans was calculated from distribution data in mice. The acute toxicity of CHIBA-1001 at a dose of 3.20 mg/kg body weight, which is more than 41,000-fold the clinical equivalent dose of [11C]CHIBA-1001, was evaluated. The mutagenicity of CHIBA-1001 was studied by a reverse mutation test in Salmonella typhimurium (Ames test). Metabolite analysis in the mouse brain was carried out by high-performance liquid chromatography. The first clinical PET imaging of α7 nAChRs with [11C]CHIBA-1001 in a normal volunteer was also performed.

Results

A suitable preparation method for [11C]CHIBA-1001 injection was established. The radiation absorbed-dose by [11C]CHIBA-1001 in humans was low enough for clinical use, and no acute toxicity or mutagenicity of CHIBA-1001 was found. Most radioactivity in the mouse brain was detected as an unchanged form, although peripherally [11C]CHIBA-1001 was degraded. We successfully performed brain imaging by PET with [11C]CHIBA-1001 in a normal volunteer. A 90-min dynamic scan showed a rapid accumulation and gradual washout of radioactivity in the brain. The highest distribution volume of [11C]CHIBA-1001 was found in the thalamus; however, regional differences in brain radioactivity were small. Peripherally, [11C]CHIBA-1001 was stable in humans: >80% of the radioactivity in plasma was detected as the unchanged form for 60 min.

Conclusions

These results demonstrate that [11C]CHIBA-1001 is a suitable radioligand to use in clinical trials for imaging α7 nAChRs in the human brain, providing acceptable dosimetry and pharmacological safety at the dose required for adequate PET imaging.

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Acknowledgments

This work was supported by grant from the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation of Japan (Grant ID: 06-46, to K.·Hashimoto and K. Ishiwata). We thank Mr. Kunpei Hayashi and Ms. Hiroko Tsukinari for technical assistance.

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Authors and Affiliations

  1. Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo, 173-0015, Japan

    Jun Toyohara, Muneyuki Sakata, Jin Wu, Masatomo Ishikawa, Keiichi Oda, Kenji Ishii & Kiichi Ishiwata

  2. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan

    Jun Toyohara, Jin Wu & Kenji Hashimoto

  3. Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan

    Masatomo Ishikawa & Masaomi Iyo

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  1. Jun Toyohara
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  2. Muneyuki Sakata
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  9. Kiichi Ishiwata
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Correspondence to Kiichi Ishiwata.

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Toyohara, J., Sakata, M., Wu, J. et al. Preclinical and the first clinical studies on [11C]CHIBA-1001 for mapping α7 nicotinic receptors by positron emission tomography. Ann Nucl Med 23, 301–309 (2009). https://doi.org/10.1007/s12149-009-0240-x

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  • DOI: https://doi.org/10.1007/s12149-009-0240-x

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