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Synthesis and evaluation of radioiodinated (S,S)-2-(α-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter

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

Abstract

Purpose

Abnormality of the brain norepinephrine transporter (NET) has been reported in several psychiatric and neuronal disorders. Since NET is an important target for the diagnosis of these diseases, the development of radiopharmaceuticals for imaging of brain NET has been eagerly awaited. In this study, we synthesized (S,S)-2-(α-(2-iodophenoxy)benzyl)morpholine [(S,S)-IPBM], a derivative of reboxetine iodinated at position 2 of the phenoxy ring, and evaluated its potential as a radiopharmaceutical for imaging brain NET using SPECT.

Methods

(S,S)-123/125I-IPBM was synthesized in a halogen exchange reaction. The affinity and selectivity of (S,S)-IPBM for NET was measured by assaying the displacement of 3H-nisoxetine and (S,S)-125I-IPBM from the binding site in rat brain membrane, respectively. The biodistribution of (S,S)-125I-IPBM was also determined in rats. Furthermore, SPECT studies with (S,S)-123I-IPBM were carried out in the common marmoset.

Results

(S,S)-125I-IPBM was prepared with high radiochemical yields (65%) and high radiochemical purity (>98%). (S,S)-IPBM showed high affinity and selectivity for NET in the binding assay experiments. In biodistribution experiments, (S,S)-125I-IPBM showed rapid uptake in the brain, and the regional cerebral distribution was consistent with the density of NET. The administration of nisoxetine, a selective NET-binding agent, decreased the accumulation of (S,S)-125I-IPBM in the brain, but the administration of selective serotonin transporter and dopamine transporter binding agents caused no significant changes in the accumulation. Moreover, (S,S)-123I-IPBM allowed brain NET imaging in the common marmoset with SPECT.

Conclusion

These results suggest that (S,S)-123I-IPBM is a potential SPECT radiopharmaceutical for imaging brain NET.

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Acknowledgements

We would like to thank Daiichi Radioisotope Laboratories Ltd., Tokyo, Japan, for providing Na123I. This study was supported in part by Grants-in-aid for General Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the 21st Century COE Program “Knowledge Information Infrastructure for Genome Science”.

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Authors and Affiliations

  1. Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan

    Naoki Kanegawa, Hiroyuki Kimura, Taku Sugita, Satomi Kajiyama, Yuji Kuge & Hideo Saji

  2. Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan

    Yasushi Kiyono

  3. Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan

    Hidekazu Kawashima

  4. Radioisotope Laboratory, Kyoto Prefectural University of Medicine, Sakyo-ku, Kyoto, Japan

    Masashi Ueda

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  1. Naoki Kanegawa
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  2. Yasushi Kiyono
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  9. Hideo Saji
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Correspondence to Hideo Saji.

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Kanegawa, N., Kiyono, Y., Kimura, H. et al. Synthesis and evaluation of radioiodinated (S,S)-2-(α-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter. Eur J Nucl Med Mol Imaging 33, 639–647 (2006). https://doi.org/10.1007/s00259-005-0017-y

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  • DOI: https://doi.org/10.1007/s00259-005-0017-y

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