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

• Published in: Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.172-177
• Main Authors: Huang, Huafan, Zhou, Hao, Li, Zejun, Wang, Xiangyun, Chu, Taiwei
• Format: Article
• Language: English
• Subjects: Alkenes - chemistry; Amines - chemistry; Animals; Biological and medical sciences; Bisnitroimidazole; Cell Line; Cell Line, Tumor; Cellular accumulation; Chromatography, High Pressure Liquid - methods; Hypoxia; Hypoxia - metabolism; in vitro studies; Medical sciences; Mice; Models, Chemical; Nitroimidazoles - chemistry; Oxidation-Reduction; Oximes - chemistry; Pharmacology. Drug treatments; PnAO; propylene; sarcoma; Technetium - chemistry; Technetium-99m; Time Factors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.11.042

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 (99mTc-1, BMS181321). Introducing a second nitroimidazole redox centre may enhance the hypoxic accumulation of the markers. In the present work, four 99mTc-1 (BMS181321, containing one 2-nitroimidazole) analogues, that is, 99mTc-2 (containing two 2-nitroimidazoles), 99mTc-3 (containing one 4-nitroimidazole), 99mTc-4 (containing two 4-nitroimidazoles) and 99mTc-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. 99mTc-3 and 99mTc-4 displayed no significant anoxic/normoxic differentials, whereas 99mTc-1 (BMS181321), 99mTc-2 and 99mTc-5 showed high anoxic cellular uptakes. The anoxic uptake of 99mTc-2 reached up to 59.0±0.9% at 4h, which was 2.4 times as that of 99mTc-1. 99mTc-2 displayed high hypoxic accumulation, indicating that introducing a second nitroimidazole redox centre, that is, 2-nitroimidazole, affected the hypoxic accumulation. Consequently, 99mTc-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.