title: Synthesis and Biological Evaluation of a New Nitroimidazole-99mTc-Complex for Imaging of Hypoxia in Mice Model.
abstract: BACKGROUND This study was specifically designed to develop a new 99mTc compound with 3-amino-4-[2-(2-methyl-5-nitro-1H-imidazol)-ethylamino]-4-oxo-butyrate (5-ntm-asp) and to verify whether this compound is feasible to be a radiopharmaceutical for hypoxic tumors. MATERIAL AND METHODS Metronidazole derivative 5-ntm-asp was synthesized and then radio-labeled by Na [99mTcO4], forming 99mTc-5-ntm-asp. Another two complexes of 99mTc-2- and 99mTc-5-nitroimidazole-iminodiacetic acid (99mTc-2-ntm-IDA and 99mTc-5-ntm-IDA) were also synthesized based on previous studies. Physicochemical properties (stability, lipophilicity, protein binding) of the compounds were compared, and we also assessed the accumulation status of the compounds within A549 cells under both hypoxic and aerobic conditions. Distribution of the complex was also studied in vivo using BALB/c nude mice that were injected with A549 cells. RESULTS Compared with 99mTc-2-ntm-IDA and 99mTc-5-ntm-IDA, 99mTc-5-ntm-asp was more stable in both phosphate-buffered saline (PBS) buffer and human plasma (P<0.05). Besides that, 99mTc-5-ntm-asp offered lower lipophilicity and protein-binding rate than the two complexes (P<0.05). During assessment of hypoxic uptake status and high hypoxic/aerobic ratio in mice injected with A549 cells, 99mTc-5-ntm-asp exhibited a more favorable profile than 9mTc-2-ntm-IDA and 99mTc-5-ntm-IDA, including uptake ratio of tumor/blood and uptake ratio of tumor/muscle. CONCLUSIONS With overall consideration of physicochemical properties and biological uptake behavior, it is feasible to use 99mTc-5-ntm-asp as an imaging agent for tumor hypoxia.
authors.affiliation: Department of Nuclear Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China (mainland).
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Nuclear Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China (mainland).
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Nuclear Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China (mainland).
authors.forename: Yanxing
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Nuclear Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China (mainland).
authors.forename: Shaozheng
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China (mainland).
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Jiangxi-OAI Joint Research Institute, Nanchang University, Nanchang, Jiangxi, China (mainland).
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Li
mesh_terms: D000072283:A549 Cells; D000818:Animals; D001682:Biological Availability; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D007098:Imino Acids; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics
chemical_list: D007098:Imino Acids; D009593:Nitroimidazoles; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C008109:iminodiacetic acid