Preparation and preliminary evaluation of a tris-metronidazole-99mTc(CO)3 complex for targeting tumor hypoxia |
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| Authors: | Madhava B. Mallia Anupam Mathur Rohit Sharma Chandan Kumar H. D. Sarma Sharmila Banerjee Ashutosh Dash |
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| Affiliation: | 1.Radiopharmaceuticals Division,Bhabha Atomic Research Centre,Mumbai,India;2.Medical and Biological Products Program,Board of Radiation and Isotope Technology,Mumbai,India;3.Radiation Biology and Health Sciences Division,Bhabha Atomic Research Centre,Mumbai,India;4.Radiation Medicine Centre,Parel, Mumbai,India |
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| 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. |
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