Synthesis and Characterization of Nitroimidazole Derivatives for (68)Ga-Labeling and Testing in Tumor Xenografted Mice

Abstract

Radiolabeled nitroimidazole (NI) derivatives have been used for imaging hypoxic tissues. We synthesized NI derivatives conjugated with bifunctional chelating agents such as 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and isothiocyanatobenzyl-NOTA (SCN-NOTA) via ethyleneamine bridge by formation of amide and thiourea bond, respectively. We proved that amide oxygen of Ga-NOTA-NI contributes to the formation of metal complex by X-ray crystallography. We labeled them with (68)Ga and found that both (68)Ga-NOTA-NI and (68)Ga- SCN-NOTA-NI were labeled in high efficiency (> 96%) and were stable at room temperature in the prepared medium and at 37 degrees C in human serum. In vitro cell uptake experiments using CHO and CT-26 cell lines showed significantly increased uptakes of both of the agents in hypoxic condition. Biodistribution study in CT-26 xenografted mice showed increasing tumor to muscle ratios. (68)Ga-NOTA-NI showed lower intestine uptake than (68)Ga-NOTA-SCN-NI due to hydrophilicity. Also, (68)Ga-NOTA-NI showed higher tumor uptake than (68)Ga-NOTA-SCN-NI in an animal PET study. In conclusion, we successfully developed (68)Ga labeled NI derivatives for hypoxic tissue imaging.