Abstract
The nitro group of 2-nitroimidazole (NIM) enters the tumor cells and is bioreductively activated and fixed in the hypoxia cells. 1,4,8,11-tetraazacyclotetradecane (N4) has shown to be a stable chelator for 99mTc. The present study was aimed to develop 99mTc-cyclam-2-nitroimidazole (99mTc-N4-NIM) for tumor hypoxia imaging. N4-NIM precursor was synthesized by reacting N4-oxalate and 1,3-dibromopropane-NIM, yielded 14% (total synthesis). Cell uptake of 99mTc-N4-NIM and 99mTc-N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates. Tissue distribution of 99mTc-N4-NIM was evaluated in breast-tumor-bearing rats at 0.5–4 hrs. Tumor oxygen tension was measured using an oxygen probe. Planar imaging was performed in the tumor-bearing rat and rabbit models. Radiochemical purity of 99mTc-N4-NIM was >96% by HPLC. Cell uptake of 99mTc-N4-NIM was higher than 99mTc-N4 in both cell lines. Biodistribution of 99mTc-N4-NIM showed increased tumor-to-blood and tumor-to-muscle count density ratios as a function of time. Oxygen tension in tumor tissue was 6–10 mmHg compared to 40–50 mmHg in normal muscle tissue. Planar imaging studies confirmed that the tumors could be visualized clearly with 99mTc-N4-NIM in animal models. Efficient synthesis of N4-NIM was achieved. 99mTc-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy.
Highlights
Recent studies demonstrated that the hypoxic environment induces more malignant neoplastic phenotypes [1]
The success of the endeavor to noninvasively detect the hypoxic fraction of tumor by nuclear molecular imaging such as single-photon emission computed tomography (SPECT) allows physicians to select patients for additional or alternative treatment regimens that may circumvent or overcome the ominous impact of tumor hypoxia and improve disease control [5]
In cells with low oxygen concentration the reoxidation is slowed, which allows further reductive reactions to take place. This leads to the formation of reactive products that could covalently bind to cell components and diffuse more slowly out of the tissue in an oxygen-dependent manner [7]. 18F-Fluoromisonidazole (18F-FMISO) and 18F-fluoroerythronitroimidazole (18F-FETNIM), 2-nitroimidazole analogues, have been used with PET to evaluate tumor Journal of Biomedicine and Biotechnology hypoxia, but the chemistries are dependent on a cyclotron to produce 18F in addition to slow serum clearances [8,9,10]
Summary
Recent studies demonstrated that the hypoxic environment induces more malignant neoplastic phenotypes [1]. The nitro group of nitroimidazole is enzymatically reduced by ribonucleoside reductase within viable hypoxic cells. This mechanism is well understood through numerous in vitro and in vivo studies from the past three decades [6]. In cells with low oxygen concentration the reoxidation is slowed, which allows further reductive reactions to take place. This leads to the formation of reactive products that could covalently bind to cell components and diffuse more slowly out of the tissue in an oxygen-dependent manner [7]. This leads to the formation of reactive products that could covalently bind to cell components and diffuse more slowly out of the tissue in an oxygen-dependent manner [7]. 18F-Fluoromisonidazole (18F-FMISO) and 18F-fluoroerythronitroimidazole (18F-FETNIM), 2-nitroimidazole analogues, have been used with PET to evaluate tumor
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