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

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.