Ga-Isothiocyanatobenzyl-tetraazacyclododecane--tetraacetic acid-2-(2-nitroimidazolyl)ethylamine

Hypoxia is found in a variety of solid tumors and leads to tumor progression and resistance to chemotherapy and radiotherapy (1-3). Tumor oxygenation is heterogeneously distributed within human tumors (4). It would be beneficial to assess tumor oxygenation before and after therapy to provide an evaluation of tumor response to treatment and an insight into new therapeutic treatments (5). Tumor oxygenation is measured invasively using computerized, polarographic, oxygen-sensitive electrodes, which is regarded as the gold standard (6). Functional and non-invasive imaging of intratumoral hypoxia has been demonstrated to be feasible for the measurement of tumor oxygenation (7). Chapman proposed the use of 2-nitroimidazoles for hypoxia imaging in 1979 (8). 2-Nitroimidazole compounds are postulated to undergo reduction in hypoxic conditions, forming highly reactive oxygen radicals that subsequently bind covalently to macromolecules inside the cells (9). In normoxic conditions, the reduced molecule is rapidly reoxidized and transported from the cell. [F]Fluoromisonidazole ([F]FMISO) is the most widely used positron emission tomography (10) tracer for imaging tumor hypoxia (7). However, it has slow clearance kinetics and a high lipophilicity, resulting in substantial background in PET scans. [F]Fluoroazomycinarabinofuranoside ([F]FAZA) is a 2-nitroimidazole with a sugar addition (11) and has been studied as a hypoxia-imaging agent, showing promising results in various tumor models in rats and mice (12, 13). Ga-Tetraazacyclododecane--tetraacetic acid-2-(2-nitroimidazolyl)ethylamine (Ga-DOTA-NI, Ga-4) and Ga-isothiocyanatobenzyl-tetraazacyclododecane--tetraacetic acid-2-(2-nitroimidazolyl)ethylamine (Ga-SCN-Bz-DOTA-NI, Ga-5) were prepared for hypoxic tissue imaging (14).