Preparation and preliminary evaluation of a tris-metronidazole-99mTc(CO)3 complex for targeting tumor hypoxia

Abstract

Conventional 99mTc-radiopharmaceuticals for the detection of tumor hypoxia generally possess a single nitroimidazole moiety. Herein, we report the synthesis and evaluation of a 99mTc-complex with three-nitroimidazole moieties in an attempt to improve hypoxic cell detection. Isocyanide derivative of metronidazole (MetroNC) was synthesized and subsequently radiolabeled with [99mTc(CO)3(H2O)3]+ precursor complex, wherein the three labile water molecules were replaced with MetroNC ligand to form a pseudo-octahedral [99mTc(CO)3(MetroNC)3]+ complex. Analysis of corresponding Re(CO)3-analog prepared in macroscopic scale confirmed the formation of expected complex. Cyclic voltammetric studies of [Re(CO)3(MetroNC)3]+ complex showed no significant change in single-electron reduction potential (SERP) of MetroNC ligand (− 0.96 V) upon forming the [Re(CO)3(MetroNC)3]+ complex (− 0.90 V). In vitro studies in Chinese hamster ovary (CHO) cells showed three-fold preferential accumulation of [99mTc(CO)3(MetroNC)3]+ complex in hypoxic cells over normoxic cells. Biodistribution studies of [99mTc(CO)3(MetroNC)3]+ complex in Swiss mice bearing fibrosarcoma tumor showed tumor uptake and steady retention till 60 min post injection. Present study constitutes a novel design approach towards development of a 99mTc-radiopharmaceutical for hypoxia imaging application, which could be extended to other potential nitroimidazole ligands.