Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
J Inorg Biochem. 2010 Feb;104(2):126-35. doi: 10.1016/j.jinorgbio.2009.10.009. Epub 2009 Oct 24.
Combination agents comprising two different pharmacophores with the same biological target have the potential to show additive or synergistic activity. Bis(thiosemicarbazonato)copper(II) complexes (e.g. (64)Cu-ATSM) and nitroimidazoles (e.g. (18)F-MISO) are classes of tracer used for the delineation of tumor hypoxia by positron emission tomography (PET). Three nitroimidazole-bis(thiosemicarbazonato)copper(II) conjugates were produced in order to investigate their potential as combination hypoxia imaging agents. Two were derived from the known bifunctional bis(thiosemicarbazone) H(2)ATSM/A and the third from the new precursor diacetyl-2-(4-N-methyl-3-thiosemicarbazone)-3-(4-N-ethylamino-3-thiosemicarbazone) - H(2)ATSM/en. Oxygen-dependent uptake studies were performed using the (64)Cu radiolabelled complexes in EMT6 carcinoma cells. All the complexes displayed appreciable hypoxia selectivity, with the nitroimidazole conjugates displaying greater selectivity than a simple propyl derivative used as a control. Participation of the nitroimidazole group in the trapping mechanism is indicated by the increased hypoxic uptake of the 2- vs. the 4-substituted (64)Cu-ATSM/A derivatives. The 2-nitroimidazole derivative of (64)Cu-ATSM/en demonstrated superior hypoxia selectivity to (64)Cu-ATSM over the range of oxygen concentrations tested. Biodistribution of the radiolabelled 2-nitroimidazole conjugates was carried out in EMT6 tumor-bearing mice. The complexes showed significantly different uptake trends in comparison to each other and previously studied Cu-ATSM derivatives. Uptake of the Cu-ATSM/en conjugate in non-target organs was considerably lower than for derivatives based on Cu-ATSM/A.
包含相同生物靶点的两种不同药效团的组合剂具有表现出相加或协同活性的潜力。双（硫代氨基甲酰基）铜（II）配合物（例如（64）Cu-ATSM）和硝基咪唑（例如（18）F-MISO）是用于通过正电子发射断层扫描（PET）描绘肿瘤缺氧的示踪剂类别。为了研究它们作为组合缺氧成像剂的潜力，制备了三种硝基咪唑-双（硫代氨基甲酰基）铜（II）缀合物。其中两种是从已知的双功能双（硫代氨基甲酰基）H（2）ATSM/A 衍生而来，第三种是从新的前体二乙酰基-2-（4-N-甲基-3-硫代氨基甲酰基）-3-（4-N-乙基氨基-3-硫代氨基甲酰基）-H（2）ATSM/en 衍生而来。使用（64）Cu 标记的配合物在 EMT6 癌细胞中进行了氧依赖性摄取研究。所有配合物均显示出相当大的缺氧选择性，硝基咪唑缀合物的选择性大于用作对照的简单丙基衍生物。硝基咪唑基团参与捕获机制的参与是通过增加 2-取代与 4-取代（64）Cu-ATSM/A 衍生物的缺氧摄取来指示的。（64）Cu-ATSM/en 的 2-硝基咪唑衍生物在测试的氧浓度范围内显示出比（64）Cu-ATSM 更高的缺氧选择性。在 EMT6 荷瘤小鼠中进行了放射性标记的 2-硝基咪唑缀合物的生物分布研究。与彼此和以前研究的 Cu-ATSM 衍生物相比，这些配合物的摄取趋势明显不同。Cu-ATSM/en 配合物在非靶器官中的摄取明显低于基于 Cu-ATSM/A 的衍生物。
