Synthesis and Biological Evaluation of Iodoglucoazomycin (I-GAZ), an Azomycin–Glucose Adduct with Putative Applications in Diagnostic Imaging and Radiotherapy of Hypoxic Tumors

Abstract

Iodoglucoazomycin (I-GAZ; N-(2-iodo-3-(6-O-glucosyl)propyl)-2-nitroimidazole), a non-glycosidic nitroimidazole–6-O-glucose adduct, was synthesized, radioiodinated, and evaluated as a substrate of glucose transporter 1 (GLUT1) for radiotheranostic (therapy+diagnostic) management of hypoxic tumors. Nucleophilic iodination of the nosylate synthon of I-GAZ followed by deprotection afforded I-GAZ in 74 % overall yield. I-GAZ was radioiodinated via ‘exchange’ labeling using [123/131I]iodide (50–70 % RCY) and then purified by Sep-Pak™ (>96 % RCP). [131I]I-GAZ was stable in 2 % ethanolic solution in sterile water for 14 days when stored at 5 °C. In cell culture, I-GAZ was found to be nontoxic to EMT-6 cells at concentrations <0.5 mm, and weakly radiosensitizing (SER 1.1 at 10 % survival of EMT-6 cells; 1.2 at 0.1 % survival in MCF-7 cells). The hypoxic/normoxic uptake ratio of [123I]I-GAZ in EMT-6 cells was 1.46 at 2 h, and under normoxic conditions the uptake of [123I]I-GAZ by EMT-6 cells was unaltered in the presence of 5 mm glucose. The biodistribution of [131I]I-GAZ in EMT-6 tumor-bearing Balb/c mice demonstrated rapid clearance from blood and extensive renal and hepatic excretion. Tumor/blood and tumor/muscle ratios reached ∼3 and 8, respectively, at 4 h post-injection. Regression analysis of the first order polynomial plots of the blood and tumor radioactivity concentrations supported a perfusion–excretion model with low hypoxia-dependent binding. [131I]I-GAZ was found to be stable in vivo, and did not deiodinate.