Synthesis and evaluation of (18)F-labeled ATP competitive inhibitors of topoisomerase II as probes for imaging topoisomerase II expression.
Synthesis and evaluation of (18)F-labeled ATP competitive inhibitors of topoisomerase II as probes for imaging topoisomerase II expression.
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DOI：
10.1016/j.ejmech.2014.09.019
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发表时间：
2014-10-30
影响因子：
6.7
通讯作者：
Lewis, Jason S.
中科院分区：
文献类型：
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作者：
Daumar, Pierre;Zeglis, Brian M.;Ramos, Nicholas;Divilov, Vadim;Sevak, Kuntal Kumar;Pillarsetty, NagaVaraKishore;Lewis, Jason S.
II型拓扑异构酶（Topo-II）是一种ATP依赖性酶，在转录、复制和染色体分离过程中至关重要，因此代表了癌症治疗的一个有吸引力的靶标。许多研究表明，对Topo-II抑制剂治疗的反应高度依赖于酶的水平和活性。因此，测量肿瘤Topo-II水平的非侵入性测定具有区分应答者与非应答者的潜力。随着开发用于正电子发射断层扫描（PET）成像的放射性氟化示踪剂的最终目标，我们设计、合成并评估了一组基于ATP竞争性Topo-II抑制剂QAP 1结构的氟化化合物。化合物18和19 b在体外测定中显示出Topo-II的抑制作用，并在SK-BR-3和MCF-7细胞系中显示出中等的Topo-II水平依赖性细胞毒性。基于这些结果，合成了这两种化合物的18F标记的类似物，并作为PET探针进行评价，用于对携带SK-BR-3异种移植物的小鼠中的Topo-II过表达进行成像。[18F]-18和[18F]-19 b由其相应的保护的甲苯磺酰化衍生物通过脱保护和随后的脱保护来合成。小动物PET成像研究表明，这两种化合物不会在肿瘤中积累，并且表现出较差的药代动力学，非常迅速地从血池中清除并代谢。从目前的研究中获得的见解肯定有助于设计和构建未来几代PET试剂，用于非侵入性描绘Topo-II表达。
Type II topoisomerase (Topo-II) is an ATP-dependent enzyme that is essential in the transcription, replication, and chromosome segregation processes and, as such, represents an attractive target for cancer therapy. Numerous studies indicate that the response to treatment with Topo-II inhibitors is highly dependent on both the levels and the activity of the enzyme. Consequently, a non-invasive assay to measure tumoral Topo-II levels has the potential to differentiate responders from non-responders. With the ultimate goal of developing a radiofluorinated tracer for positron emission tomography (PET) imaging, we have designed, synthesized, and evaluated a set of fluorinated compounds based on the structure of the ATP-competitive Topo-II inhibitor QAP1. Compounds 18 and 19b showed inhibition of Topo-II in in vitro assays and exhibited moderate, Topo-II level dependent cytotoxicity in SK-BR-3 and MCF-7 cell lines. Based on these results, 18F-labeled analogs of these two compounds were synthesized and evaluated as PET probes for imaging Topo-II overexpression in mice bearing SK-BR-3 xenografts. [18F]-18 and [18F]-19b were synthesized from their corresponding protected tosylated derivatives by fluorination and subsequent deprotection. Small animal PET imaging studies indicated that both compounds do not accumulate in tumors and exhibit poor pharmacokinetics, clearing from the blood pool very rapidly and getting metabolized over. The insights gained from the current study will surely aid in the design and construction of future generations of PET agents for the non-invasive delineation of Topo-II expression.
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DOI：
10.1038/nrc2607
发表时间：
2009-05
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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影响因子：
15
作者：
Reddy, Gadarla Randheer;Thompson, Walter C.;Miller, Stephen C.
通讯作者：
Miller, Stephen C.
影响因子：
8.8
作者：
Turley, H;Comley, M;Houlbrook, S;Nozaki, N;Kikuchi, A;Hickson, ID;Gatter, K;Harris, AL
通讯作者：
Harris, AL
影响因子：
45.3
作者：
Press, Michael F.;Sauter, Guido;Slamon, Dennis J.
通讯作者：
Slamon, Dennis J.
DOI：
10.1038/nrc2608
发表时间：
2009-05
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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