Nitroimidazole conjugates of bis(thiosemicarbazonato)64Cu(II) - Potential combination agents for the PET imaging of hypoxia.
Nitroimidazole conjugates of bis(thiosemicarbazonato)64Cu(II) - Potential combination agents for the PET imaging of hypoxia.
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DOI：
10.1016/j.jinorgbio.2009.10.009
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发表时间：
2010-02
影响因子：
3.9
通讯作者：
Dilworth, Jonathan R.
中科院分区：
文献类型：
--
作者：
Bonnitcha, Paul D.;Bayly, Simon R.;Theobald, Mark B. M.;Betts, Helen M.;Lewis, Jason S.;Dilworth, Jonathan R.
由具有相同生物靶点的两种不同药效团组成的联合制剂具有潜在的加性或协同活性。双（硫代氨基脲）铜（II）配合物（如64Cu-ATSM）和硝基咪唑（如18F-MISO）是一类用于正电子发射断层扫描（PET）描绘肿瘤缺氧的示踪剂。制备了三种硝基咪唑-双（硫代氨基脲）铜（II）偶联物，以研究它们作为联合缺氧显像剂的潜力。其中两个是从已知的双功能双（硫代氨基脲）H2ATSM/A中分离得到的，第三个是从新的前体二乙酰基-2-（4- n -甲基-3-硫代氨基脲）-3-（4- n -乙基氨基-3-硫代氨基脲）- H2ATSM/en中分离得到的。使用64Cu放射性标记复合物在EMT6癌细胞中进行氧依赖摄取研究。所有配合物都表现出明显的低氧选择性，其中硝基咪唑偶联物比一个简单的丙基衍生物具有更高的选择性。与4取代64Cu-ATSM/A衍生物相比，2-取代64Cu-ATSM/A衍生物的缺氧吸收率增加，表明硝基咪唑基团参与了捕获机制。在不同的氧浓度范围内，64Cu-ATSM/en的2-硝基咪唑衍生物对64Cu-ATSM具有较好的低氧选择性。研究了放射性标记的2-硝基咪唑偶联物在EMT6荷瘤小鼠体内的生物分布。这些配合物与其他配合物以及先前研究的Cu-ATSM衍生物相比，表现出明显不同的吸收趋势。Cu-ATSM/en偶联物在非靶器官中的摄取明显低于基于Cu-ATSM/A的衍生物。
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. 64Cu-ATSM) and nitroimidazoles (e.g. 18F-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) H2ATSM/A and the third from the new precursor diacetyl-2-(4-N-methyl-3-thiosemicarbazone)-3-(4-N-ethylamino-3-thiosemicarbazone) – H2ATSM/en. Oxygen-dependent uptake studies were performed using the 64Cu 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 64Cu-ATSM/A derivatives. The 2-nitroimidazole derivative of 64Cu-ATSM/en demonstrated superior hypoxia selectivity to 64Cu-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.
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影响因子：
3.9
作者：
Dietz DW;Dehdashti F;Grigsby PW;Malyapa RS;Myerson RJ;Picus J;Ritter J;Lewis JS;Welch MJ;Siegel BA
通讯作者：
Siegel BA
影响因子：
3
作者：
ERLANSON, M;DANIELSZOLGAY, E;CARLSSON, J
通讯作者：
CARLSSON, J
影响因子：
16.6
作者：
Betts, Helen M.;Barnard, Peter J.;Holland, Jason P.
通讯作者：
Holland, Jason P.
影响因子：
4.9
作者：
Dearling, JLJ;Lewis, JS;Blower, PJ
通讯作者：
Blower, PJ
影响因子：
7.3
作者：
HAY, MP;WILSON, WR;DENNY, WA
通讯作者：
DENNY, WA