Syntheses of 2-nitroimidazole derivatives conjugated with 1,4,7-triazacyclononane- N, N ′-diacetic acid labeled with F-18 using an aluminum complex method for hypoxia imaging

Hypoxia imaging is important for diagnosis of ischemic diseases, and thus various ¹⁸F-labeled radiopharmaceuticals have been developed. However, ¹⁸F-labeling requires multistep procedures including azeotropic distillation, which is complicated and difficult to automate. Recently, ¹⁸F-labeling method using Al-F complex in aqueous solution was devised that offered a straightforward ¹⁸F-labeling procedure. We synthesized nitroimidazole derivatives conjugated with 1,4,7-triazacyclononane- 1,4-diacetic acid (NODA) that can be labeled with ¹⁸F using Al-F complex and examined their radiochemistries, in vitro and in vivo biological properties, and animal PET imaging characteristics. We found that the synthesized derivatives have excellent ¹⁸F-labeling efficiencies, high stabilities, specific uptakes in cultured hypoxic tumor cells, and high tumor to nontumor ratios in xenografted mice. Furthermore, the derivatives were labeled with ¹⁸F in a straightforward manner within 15 min at high labeling efficiencies and radiochemical purities. In conclusion, ¹⁸F-labeled NODA-nitroimidazole conjugates were developed and proved to be promising hypoxia PET agents.