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

Naoki Kanegawa, Yasushi Kiyono, Hiroyuki Kimura, Taku Sugita, Satomi Kajiyama, Hidekazu Kawashima, Masashi Ueda, Yuji Kuge, Hideo Saji

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)639-647
Number of pages9
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume33
Issue number6
DOIs
Publication statusPublished - Jun 2006
Externally publishedYes

Fingerprint

Norepinephrine Plasma Membrane Transport Proteins
Neuroimaging
nisoxetine
Single-Photon Emission-Computed Tomography
Radiopharmaceuticals
Brain
Callithrix
morpholine
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Halogens
Psychiatry
Binding Sites

Keywords

  • (S,S)-2-(a-(2-iodo- phenoxy)benzyl)morpholine
  • Brain
  • Norepinephrine transporter
  • Radioiodination
  • SPECT

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology

Cite this

Synthesis and evaluation of radioiodinated (S,S)-2-(α-(2-iodophenoxy) benzyl)morpholine for imaging brain norepinephrine transporter. / Kanegawa, Naoki; Kiyono, Yasushi; Kimura, Hiroyuki; Sugita, Taku; Kajiyama, Satomi; Kawashima, Hidekazu; Ueda, Masashi; Kuge, Yuji; Saji, Hideo.

In: European Journal of Nuclear Medicine and Molecular Imaging, Vol. 33, No. 6, 06.2006, p. 639-647.

Research output: Contribution to journalArticle

Kanegawa, Naoki ; Kiyono, Yasushi ; Kimura, Hiroyuki ; Sugita, Taku ; Kajiyama, Satomi ; Kawashima, Hidekazu ; Ueda, Masashi ; Kuge, Yuji ; Saji, Hideo. / Synthesis and evaluation of radioiodinated (S,S)-2-(α-(2-iodophenoxy) benzyl)morpholine for imaging brain norepinephrine transporter. In: European Journal of Nuclear Medicine and Molecular Imaging. 2006 ; Vol. 33, No. 6. pp. 639-647.
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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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T1 - Synthesis and evaluation of radioiodinated (S,S)-2-(α-(2-iodophenoxy) benzyl)morpholine for imaging brain norepinephrine transporter

AU - Kanegawa, Naoki

AU - Kiyono, Yasushi

AU - Kimura, Hiroyuki

AU - Sugita, Taku

AU - Kajiyama, Satomi

AU - Kawashima, Hidekazu

AU - Ueda, Masashi

AU - Kuge, Yuji

AU - Saji, Hideo

PY - 2006/6

Y1 - 2006/6

N2 - 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.

AB - 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.

KW - (S,S)-2-(a-(2-iodo- phenoxy)benzyl)morpholine

KW - Brain

KW - Norepinephrine transporter

KW - Radioiodination

KW - SPECT

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