title: 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.
abstract: 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 ((99m)Tc-1, BMS181321). Introducing a second nitroimidazole redox centre may enhance the hypoxic accumulation of the markers. In the present work, four (99m)Tc-1 (BMS181321, containing one 2-nitroimidazole) analogues, that is, (99m)Tc-2 (containing two 2-nitroimidazoles), (99m)Tc-3 (containing one 4-nitroimidazole), (99m)Tc-4 (containing two 4-nitroimidazoles) and (99m)Tc-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. (99m)Tc-3 and (99m)Tc-4 displayed no significant anoxic/normoxic differentials, whereas (99m)Tc-1 (BMS181321), (99m)Tc-2 and (99m)Tc-5 showed high anoxic cellular uptakes. The anoxic uptake of (99m)Tc-2 reached up to 59.0±0.9% at 4h, which was 2.4 times as that of (99m)Tc-1. (99m)Tc-2 displayed high hypoxic accumulation, indicating that introducing a second nitroimidazole redox centre, that is, 2-nitroimidazole, affected the hypoxic accumulation. Consequently, (99m)Tc-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.
authors.affiliation: Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Huafan
authors.initials: H
authors.lastname: Huang
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.forename: Zejun
authors.initials: Z
authors.lastname: Li
authors.forename: Xiangyun
authors.initials: X
authors.lastname: Wang
authors.forename: Taiwei
authors.initials: T
authors.lastname: Chu
mesh_terms: D000475:Alkenes / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D000860:Hypoxia / Q000378:metabolism*; D051379:Mice; D008956:Models, Chemical; D009593:Nitroimidazoles / Q000737:chemistry*; D010084:Oxidation-Reduction; D010091:Oximes / Q000737:chemistry; D013667:Technetium / Q000737:chemistry*; D013997:Time Factors
chemical_list: D000475:Alkenes; D000588:Amines; D009593:Nitroimidazoles; D010091:Oximes; D013667:Technetium; C013658:propylene