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Development of (99m)Tc-N4-NIM for molecular imaging of tumor hypoxia.

Ali MS, Kong FL, Rollo A, Mendez R, Kohanim S, Smith DL, Yang DJ - J. Biomed. Biotechnol. (2012)

Bottom Line: Cell uptake of (99m)Tc-N4-NIM was higher than (99m)Tc-N4 in both cell lines.Biodistribution of (99m)Tc-N4-NIM showed increased tumor-to-blood and tumor-to-muscle count density ratios as a function of time.Efficient synthesis of N4-NIM was achieved. (99m)Tc-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. mohammad.ali@mdanderson.org

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 (99m)Tc. The present study was aimed to develop (99m)Tc-cyclam-2-nitroimidazole ((99m)Tc-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 (99m)Tc-N4-NIM and (99m)Tc-N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates. Tissue distribution of (99m)Tc-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 (99m)Tc-N4-NIM was >96% by HPLC. Cell uptake of (99m)Tc-N4-NIM was higher than (99m)Tc-N4 in both cell lines. Biodistribution of (99m)Tc-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 (99m)Tc-N4-NIM in animal models. Efficient synthesis of N4-NIM was achieved. (99m)Tc-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy.

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Synthetic scheme of N4-NIM.
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fig1: Synthetic scheme of N4-NIM.

Mentions: The synthetic scheme of N4-NIM is shown in Figure 1. One molar equivalent of NaOH 1 M (0.3864 g, 9.66 mmol, 9.66 mL) was added to 2-nitroimidazole (1.09 g, 9.66 mmol) and warmed 30 minutes at 50°C to dissolve it. If the compound was not dissolved in the solution then NaOH was added drop by drop until the solid was dissolved completely and we continue heating for 15 minutes more. Water was removed on rotary evaporator. Crude compound was dissolved in minimum quantity of water, filtered, and lyophilized. Yield: 5.31 g, (90%).


Development of (99m)Tc-N4-NIM for molecular imaging of tumor hypoxia.

Ali MS, Kong FL, Rollo A, Mendez R, Kohanim S, Smith DL, Yang DJ - J. Biomed. Biotechnol. (2012)

Synthetic scheme of N4-NIM.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376529&req=5

fig1: Synthetic scheme of N4-NIM.
Mentions: The synthetic scheme of N4-NIM is shown in Figure 1. One molar equivalent of NaOH 1 M (0.3864 g, 9.66 mmol, 9.66 mL) was added to 2-nitroimidazole (1.09 g, 9.66 mmol) and warmed 30 minutes at 50°C to dissolve it. If the compound was not dissolved in the solution then NaOH was added drop by drop until the solid was dissolved completely and we continue heating for 15 minutes more. Water was removed on rotary evaporator. Crude compound was dissolved in minimum quantity of water, filtered, and lyophilized. Yield: 5.31 g, (90%).

Bottom Line: Cell uptake of (99m)Tc-N4-NIM was higher than (99m)Tc-N4 in both cell lines.Biodistribution of (99m)Tc-N4-NIM showed increased tumor-to-blood and tumor-to-muscle count density ratios as a function of time.Efficient synthesis of N4-NIM was achieved. (99m)Tc-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. mohammad.ali@mdanderson.org

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 (99m)Tc. The present study was aimed to develop (99m)Tc-cyclam-2-nitroimidazole ((99m)Tc-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 (99m)Tc-N4-NIM and (99m)Tc-N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates. Tissue distribution of (99m)Tc-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 (99m)Tc-N4-NIM was >96% by HPLC. Cell uptake of (99m)Tc-N4-NIM was higher than (99m)Tc-N4 in both cell lines. Biodistribution of (99m)Tc-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 (99m)Tc-N4-NIM in animal models. Efficient synthesis of N4-NIM was achieved. (99m)Tc-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy.

Show MeSH
Related in: MedlinePlus