Effect of a second nitroimidazole redox centre on the accumulation of a hypoxia marker: Synthesis and in vitro evaluation of 99mTc-labeled bisnitroimidazole propylene amine oxime complexes

Up to now, most of the hypoxia markers contain only one nitroimidazole redox centre, such as Oxo[[3,3,9,9-tetramethyl-1-(2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane-2,10-dione dioximato] (3-)-N, N', N '', N''']technetium (Tc-99m-1, BMS181321). Introducing a second nitroimidazole redox centre may enhance the hypoxic accumulation of the markers. In the present work, four Tc-99m-1 (BMS181321, containing one 2-nitroimidazole) analogues, that is, Tc-99m-2 (containing two 2-nitroimidazoles), Tc-99m-3 (containing one 4-nitroimidazole), Tc-99m-4 (containing two 4-nitroimidazoles) and Tc-99m-5 (containing both a 2-nitroimidazole and a 4-nitroimidazole) were synthesized, and the hypoxic accumulation was evaluated in vitro using murine sarcoma S180 cells. Tc-99m-3 and Tc-99m-4 displayed no significant anoxic/normoxic differentials, whereas Tc-99m-1 (BMS181321), Tc-99m-2 and Tc-99m-5 showed high anoxic cellular uptakes. The anoxic uptake of Tc-99m-2 reached up to 59.0 +/- 0.9% at 4 h, which was 2.4 times as that of Tc-99m-1. Tc-99m-2 displayed high hypoxic accumulation, indicating that introducing a second nitroimidazole redox centre, that is, 2-nitroimidazole, affected the hypoxic accumulation. Consequently, Tc-99m-2 may serve as a viable candidate for hypoxia marker. This finding may eventually lead to the development of compounds containing multi-redox centres as hypoxia markers. (C) 2011 Elsevier Ltd. All rights reserved.