Development of (99m)Tc-N4-NIM for molecular imaging of tumor hypoxia.
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.
Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. mohammad.ali@mdanderson.org
Mohammad S
MS
Ali
Fan-Lin
FL
Kong
Alex
A
Rollo
Richard
R
Mendez
Saady
S
Kohanim
Daniel Lee
DL
Smith
David J
DJ
Yang
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D057054:Molecular Imaging / Q000379:methods; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D009593:Nitroimidazoles / Q000737:chemistry / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D010100:Oxygen / Q000378:metabolism; D011817:Rabbits; D011849:Radioactive Tracers; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D059016:Tumor Microenvironment
D006573:Heterocyclic Compounds, 1-Ring; D009593:Nitroimidazoles; D015609:Organotechnetium Compounds; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals; C045773:technetium Tc 99m cyclam; D010100:Oxygen