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Synthesis and characterization in monkey of [11C]SP203 as a radioligand for imaging brain metabotropic glutamate 5 receptors

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

[18F]SP203 (3-fluoro-5-(2-(2-([18F]fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile) is an effective high-affinity and selective radioligand for imaging metabotropic 5 receptors (mGluR5) in human brain with PET. To provide a radioligand that may be used for more than one scanning session in the same subject in a single day, we set out to label SP203 with shorter-lived 11C (t 1/2 = 20.4 min) and to characterize its behavior as a radioligand with PET in the monkey.

Methods

Iodo and bromo precursors were obtained by cross-coupling 2-fluoromethyl-4-((trimethylsilyl)ethynyl)-1,3-thiazole with 3,5-diiodofluorobenzene and 3,5-dibromofluorobenzene, respectively. Treatment of either precursor with [11C]cyanide ion rapidly gave [11C]SP203, which was purified with high-performance liquid chromatography. PET was used to measure the uptake of radioactivity in brain regions after injecting [11C]SP203 intravenously into rhesus monkeys at baseline and under conditions in which mGluR5 were blocked with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP). The emergence of radiometabolites in monkey blood in vitro and in vivo was assessed with radio-HPLC. The stability of [11C]SP203 in human blood in vitro was also measured.

Results

The iodo precursor gave [11C]SP203 in higher radiochemical yield (>98 %) than the bromo precursor (20–52 %). After intravenous administration of [11C]SP203 into three rhesus monkeys, radioactivity peaked early in brain (average 12.5 min) with a regional distribution in rank order of expected mGluR5 density. Peak uptake was followed by a steady decline. No radioactivity accumulated in the skull. In monkeys pretreated with MTEP before [11C]SP203 administration, radioactivity uptake in brain was again high but then declined more rapidly than in the baseline scan to a common low level. [11C]SP203 was unstable in monkey blood in vitro and in vivo, and gave predominantly less lipophilic radiometabolites. By contrast, [11C]SP203 was stable in human blood in vitro.

Conclusion

[11C]SP203 emulates [18F]SP203 with regard to providing a sizeable mGluR5-specific signal in monkey brain, and advantageously avoids troublesome accumulation of radioactivity in bone. Although [11C]SP203 is unsuitable for mGluR5 quantification in monkey brain, its evaluation as a PET radioligand for studying human brain mGluR5 is nevertheless warranted.

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Acknowledgments

This research was supported by the Intramural Research Program of the National Institutes of Health (National Institute of Mental Health). We thank the National Institutes of Health Clinical PET Center (Chief: Dr. Peter Herscovitch) for the production of hydrogen [11C]cyanide and Dr. H. Umesha Shetty for mass spectrometry.

Conflicts of interest

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Authors and Affiliations

  1. Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Rm. B3 C346A, 10 Center Drive, Bethesda, MD, 20892, USA

    Fabrice G. Siméon, Jeih-San Liow, Yi Zhang, Jinsoo Hong, Robert L. Gladding, Sami S. Zoghbi & Robert B. Innis

  2. Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA

    Victor W. Pike

Authors
  1. Fabrice G. Siméon
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  2. Jeih-San Liow
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  3. Yi Zhang
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  4. Jinsoo Hong
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  6. Sami S. Zoghbi
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  7. Robert B. Innis
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  8. Victor W. Pike
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Correspondence to Victor W. Pike.

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Siméon, F.G., Liow, JS., Zhang, Y. et al. Synthesis and characterization in monkey of [11C]SP203 as a radioligand for imaging brain metabotropic glutamate 5 receptors. Eur J Nucl Med Mol Imaging 39, 1949–1958 (2012). https://doi.org/10.1007/s00259-012-2205-x

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  • DOI: https://doi.org/10.1007/s00259-012-2205-x

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