Synthesis and evaluation of 4-bromo-1-(3-[18F]fluoropropyl)-2- nitroimidazole with a low energy LUMO orbital designed as brain hypoxia-targeting imaging agent

Fumihiko Yamamoto, Mizuho Aoki, Yoshiya Furusawa, Koichi Ando, Yasuo Kuwabara, Kouji Masuda, Shigeki Sasaki, Minoru Maeda

Research output: Contribution to journalArticle

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Abstract

In order to develop new imaging markers for brain hypoxia, 4-bromo-1-(3-fluoropropyl)-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 18F-labeled 4-BrFPN (4-Br18FPN) was achieved by [18F]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-Br18FPN in normal rat, were studied. The initial uptake into rat brain of 4-Br 18FPN was significantly higher relative to 18F-labeled FMISO (18FMISO), followed by a rapid washout from the brain. The tumor uptake of 4-Br18FPN was somewhat enhanced compared to those obtained with 18FMISO and 18F-labeled FPN ( 18FPN), but with lower tumor localization than 18FMISO. 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-Br18FPN, 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.

Original languageEnglish
Pages (from-to)616-621
Number of pages6
JournalBiological and Pharmaceutical Bulletin
Volume25
Issue number5
DOIs
Publication statusPublished - May 1 2002

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Brain Hypoxia
Neoplasms
Muscles
Nitroimidazoles
Hydralazine
Methylcholanthrene
Fluorine
Fibrosarcoma
Brain
Tissue Distribution
4-bromo-1-(3-fluoropropyl)-2-nitroimidazole
Radio
Fluorides
Arginine
fluoromisonidazole
Ions
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

Synthesis and evaluation of 4-bromo-1-(3-[18F]fluoropropyl)-2- nitroimidazole with a low energy LUMO orbital designed as brain hypoxia-targeting imaging agent. / Yamamoto, Fumihiko; Aoki, Mizuho; Furusawa, Yoshiya; Ando, Koichi; Kuwabara, Yasuo; Masuda, Kouji; Sasaki, Shigeki; Maeda, Minoru.

In: Biological and Pharmaceutical Bulletin, Vol. 25, No. 5, 01.05.2002, p. 616-621.

Research output: Contribution to journalArticle

Yamamoto, Fumihiko ; Aoki, Mizuho ; Furusawa, Yoshiya ; Ando, Koichi ; Kuwabara, Yasuo ; Masuda, Kouji ; Sasaki, Shigeki ; Maeda, Minoru. / Synthesis and evaluation of 4-bromo-1-(3-[18F]fluoropropyl)-2- nitroimidazole with a low energy LUMO orbital designed as brain hypoxia-targeting imaging agent. In: Biological and Pharmaceutical Bulletin. 2002 ; Vol. 25, No. 5. pp. 616-621.
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AU - Aoki, Mizuho

AU - Furusawa, Yoshiya

AU - Ando, Koichi

AU - Kuwabara, Yasuo

AU - Masuda, Kouji

AU - Sasaki, Shigeki

AU - Maeda, Minoru

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