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Journal of Biomedicine and Biotechnology
Volume 2012 (2012), Article ID 828139, 9 pages
Research Article

Development of 𝟗 𝟗 𝐦 𝐓 𝐜 -N4-NIM for Molecular Imaging of Tumor Hypoxia

1Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

Received 31 January 2012; Revised 24 March 2012; Accepted 1 April 2012

Academic Editor: Yasuhisa Fujibayashi

Copyright © 2012 Mohammad S. Ali et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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 9 9 m T c . The present study was aimed to develop 9 9 m T c -cyclam-2-nitroimidazole ( 9 9 m T c -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 9 9 m T c -N4-NIM and 9 9 m T c -N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates. Tissue distribution of 9 9 m T c -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 9 9 m T c -N4-NIM was >96% by HPLC. Cell uptake of 9 9 m T c -N4-NIM was higher than 9 9 m T c -N4 in both cell lines. Biodistribution of 9 9 m T c -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 9 9 m T c -N4-NIM in animal models. Efficient synthesis of N4-NIM was achieved. 9 9 m T c -N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy.