Preparation and biological evaluation of (99m)Tc-labelled phenazine dioxides as potential tracers for hypoxia imaging.

Abstract

The aim of this study was to investigate the capability of phenazine dioxides, recognized bioreductive antitumour agents, as carriers for (99m)Tc in order to generate potential theranostic radiopharmaceuticals towards hypoxic solid tumours. Two different phenazine dioxides were used as ligands for the (99m)Tc-tricarbonyl core in order to prepare the potential radiopharmaceuticals. The main physicochemical and biological properties were evaluated. Biodistribution of the two radiotracers was studied at different time points after intravenous injection in tumour bearing animals. Both compounds were obtained in high yield and radiochemichal purity. They were stable in labelling milieu, in human plasma and in the presence of histidine. Biodistribution studies in mice were characterized by slow blood clearance and persistent liver uptake, results that correlate with the values of lipophilicities and protein binding. Both the complexes showed good tumour uptake, which remained constant during the studied period. Tumour/muscle ratios proved very favourable, comparable to those of FMISO in the same animal model. On the other hand, tumour/blood ratios were low due to high blood uptake. The use of phenazine dioxides as ligands for the preparation of potential (99m)Tc-radiopharmaceuticals towards solid tumours is possible since tumour uptake and retention are promising although high blood and liver uptake are drawbacks worth consideration.