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 F-18-labeled radiopharmaceuticals have been developed. However, F-18-labeling requires multistep procedures including azeotropic distillation, which is complicated and difficult to automate. Recently, F-18-labeling method using Al-F complex in aqueous solution was devised that offered a straightforward F-18-labeling procedure. We synthesized nitroimidazole derivatives conjugated with 1,4,7-triazacyclononane-1,4-diacetic acid (NODA) that can be labeled with F-18 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 F-18-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 F-18 in a straightforward manner within 15 min at high labeling efficiencies and radiochemical purities. In conclusion, F-18-labeled NODA-nitroimidazole conjugates were developed and proved to be promising hypoxia PET agents.