Synthesis and Evaluation of 4-Bromo-1-(3-[^<18>F]fluoropropyl)-2-nitroimidazole with a Low Energy LUMO Orbital Designed as Brain Hypoxia-Targeting Imaging Agent

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概要

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• In order to develop new imaging markers for brain hypoxia, 4-bromo-1-(3-fiuoropropyl)-2-nitroimidazole (4-BrFPN) was designed based on molecular orbital calculations, synthesized and labeled with fluorine-18 as a lipophilic nitroimidazole analog with a lower energy LUMO orbital than those for fluoromisonidazole (FMISO) and 1-(3-fluoropropyl)-2-nitroimidazole (FPN). In an in vitro radiosensitization study, the sensitizer enhancement ratio for 4-BrFPN was found to be 1.65 at a 1 mM concentration, in comparison to 1.81 for FMISO. The preparation of ^<18>F-lableled 4-BrFPN (4-Br^<18>FPN) was achieved by [^<18>F]fluoride ion displacement reaction of the tosylate precursor, in a reasonable radiochemical yield (33%, not corrected for decay). Metabolites in tumor and muscle extracts from methylcholanthrene-induced fibrosarcoma mice, as well as the tissue distribution of 4-Br^<18>FPN in normal rats, were studied. The initial uptake into rat brain of 4-Br^<18>FPN was significantly higher relative to ^<18>F-labeled FMISO (^<18>FMISO), followed by a rapid washout from the brain. The tumor uptake of 4-Br^<18>FPN was somewhat enhanced compared to those obtained with ^<18>FMISO and ^<18>F-labeled FPN (^<18>), but with lower tumor localization than ^<18>FMISO. Analyses of tumor and muscle extracts showed metabolites remaining base line on the radio-TLC plates, and they were produced to a greater extent in tumor than muscle. The use of two drugs which increase hypoxic cell fraction in tumor, hydralazine or nitro-L-arginine, produced a significant increase in tumor levels of 4-Br^<18>FPN suggestive of a hypoxic mechanism of accumulation. The results imply that lowering of the LUMO energy of a molecule alone is not sufficient to improve its biodistribution properties for better imaging of regions of hypoxia.

• 社団法人日本薬学会の論文
• 2002-05-01

著者

• 安藤 興一

  学振科技特

• 安藤 興一

  Natl. Instit. Rad. Sci. Med.

• FURUSAWA Yoshiya

  National Institute of Radiological Sciences

• FUTAMI Yasuyuki

  Shizuoka Cancer Center

• Futami Yasuyuki

  茨城県立医療大学 放射線技術科学科

• Futami Yasuyuki

  The Institute Of Physics University Of Tsukuba

• Futami Yasuyuki

  Dvisin Of Accelerator Physics And Engineering National Institite Of Radiological Sciences Chiba Japa

• MAEDA Minoru

  Graduate School of Pharmaceutical Sciences, Kyushu University

• YAMAMOTO Fumihiko

  Faculty of Pharmaceutical Sciences, Kyushu University

• KUWABARA Yasuo

  Faculty of Medical Sciences, Kyushu University

• MAEDA Minoru

  Faculty of Pharmaceutical Sciences, Kyushu University

• Ando K

  Division Of Health Sciences Graduate School Of Medicine Osaka University

• Kuwabara Yasuo

  Department Of Radiology Faculty Of Medicine Fukuoka University

• Kuwabara Yasuo

  Dep. Of Radiology School Of Medicine Fukuoka Univ.

• Aoki M

  Heavy-ion Radiobiology Research Group National Institute Of Radiological Sciences

• Aoki Mizuho

  Clinical Radiation Biology and International Space Radiation Laboratory,National Institute of Radiol

• Furusawa Yoshiya

  Clinical Radiation Biology and International Space Radiation Laboratory,National Institute of Radiol

• Ando Koichi

  Clinical Radiation Biology and International Space Radiation Laboratory,National Institute of Radiol

• Masuda Kouji

  Faculty of Medicine, Kyushu University

• Sasaki Shigeki

  Faculty of Pharmaceutical Sciences, Kyushu University

• 佐々木 茂貴

  Faculty Of Pharmaceutical Sciences Kyushu University

• Sasaki Shigeki

  Faculty Of Pharmaceutical Sciences Kyushu University

• Ando Koichi

  Department Of Technical Support And Development Natl. Inst. Radiol. Sci.

• Ando Koichi

  Space And Particle Radiation Science Research Group National Institute Of Radiological Sciences

• Masuda K

  Showa Pharmaceutical University

• Kuwabara Yasuo

  Graduate School Of Medical Sciences Kyushu University

• Ando Koichi

  Division Of Health Sciences Graduate School Of Medicine Osaka University

• Masuda Katsuyoshi

  Suntory Institute For Bioorganic Research Wakayamadai

• Maeda Minoru

  Optical Measurement Technology Development Co. Ltd.

• Maeda Minoru

  Graduate School Of Pharmaceutical Sciences Kyushu University

• Yamamoto Fumihiko

  Graduate School Of Pharmaceutical Sciences Kyushu University:crest Japan Sceicne And Technology Corp

• Yamamoto Fumihiko

  Graduate School Of Pharmaceutical Sciences Kyushu University

• Furusawa Yoshiya

  高エネルギー加速器研究機構物質構造科学研究所

• Aoki Mizuho

  Heavy-ion Radiobiol. Res. Gr. Natl. Inst. Radiol. Sci.

• Masuda K

  Shionogi Research Laboratories Shionogi & Co. Ltd.

• Masuda Kouji

  Department Of Clinical Radiology Graduate School Of Medical Sciences Kyushu University

• Maeda M

  Graduate School Of Pharmaceutical Sciences Kyushu University

• Kuwabara Y

  Department Of Radiology Faculty Of Medicine Fukuoka University

• Maeda M

  Tokyo Tanabe Co. Ltd. Tokyo Jpn

• Yasumori Kotaro

  Neuroradiology Cerebrovascular Center And Clinical Research Institute National Kyushu Medical Center

• Masuda Kouji

  Department Of Clinical Radiology Garaduate School Of Medical Sciences Kyushu University

• Kuwabara Yasuo

  Kyushu Univ. Hospital Fukuoka Jpn

• Ando Koichi

  Clinical Radiation Biology And International Space Radiation Laboratory National Institute Of Radiol

• Furusawa Yoshiya

  Div. Of Accelerator Res. Natl. Inst. Of Radiol. Sci.

• Kimura Masahiko

  Department Of Clinical Radiology Garaduate School Of Medical Sciences Kyushu University

• Maeda Minoru

  Faculty Of Pharmaceutical Sciences Kyushu University

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