Development of ⁶⁸Ga-labeled Mono-, Bis- and Tris-nitroimidazole Derivatives for Hypoxia Imaging

We report a series of ⁶⁸Ga-labeled hypoxia imaging agents for positron emission tomography (PET) based on mono-, bis- and tri-nitroimidazole conjugates with a bifunctional chelating (BFC) agent 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid] (TRAP). The obtained conjugates were efficiently labeled with ⁶⁸Ga within 10 min at 95℃ with high radiochemical yields (>96 %). The ⁶⁸Ga-labeled derivatives were found to be stable at room temperature in the prepared medium and at 37℃ in human serum up to 4 h. The prepared derivatives were hydrophilic than the standard hypoxia imaging agent, [¹⁸F]FMISO. The development of hydrophilic hypoxia imaging agents are needed to overcome some of the limitations of [¹⁸F]FMISO, such as nonspecific retention in liver and gastrointestinal track. In conclusion, we successfully developed the novel multivalent ⁶⁸Ga labeled nitroimidazole derivatives for hypoxic tissue imaging.