Synthesis of ⁶⁸Ga-labeled DOTA-nitroimidazole derivatives and their feasibilities as hypoxia imaging PET tracers

The imaging of hypoxia is important for therapeutic decision making in various diseases. ⁶⁸Ga is an important radionuclide for positron emission tomography (PET), and its usage is increasing, due to the development of the ⁶⁸Ge/⁶⁸Ga-generator. In the present study, the authors synthesized two nitroimidazole derivatives by conjugating nitroimidazole and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) via an amide bond (4) and a thiourea bond (5). Both derivatives were labeled with ⁶⁸Ga with high labeling efficiency and were stable after labeling. The low partition coefficients (log P) of ⁶⁸Ga-4 (-4.6) and ⁶⁸Ga-5 (-4.5) demonstrated the hydrophilic natures of the derivatives, and both showed higher uptake in cancer cell lines cultured under hypoxic condition than under normoxic condition. However, ⁶⁸Ga-5 showed higher liver uptake than ⁶⁸Ga-4 in a biodistribution study due to higher lipophilicity. In an animal PET study, ⁶⁸Ga-4 showed higher standard uptake values (SUV) in tumors than ⁶⁸Ga-5 in mice xenografted with CT-26 mouse colon cancer cells.