Daumar Pierre, Zeglis Brian M, Ramos Nicholas, Divilov Vadim, Sevak Kuntal Kumar, Pillarsetty NagaVaraKishore, Lewis Jason S
Department of Radiology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Department of Radiology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Eur J Med Chem. 2014 Oct 30;86:769-81. doi: 10.1016/j.ejmech.2014.09.019. Epub 2014 Sep 8.
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, (18)F-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. [(18)F]-18 and [(18)F]-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.
II型拓扑异构酶（Topo-II）是一种依赖ATP的酶，在转录、复制和染色体分离过程中必不可少，因此是癌症治疗的一个有吸引力的靶点。大量研究表明，对Topo-II抑制剂治疗的反应高度依赖于该酶的水平和活性。因此，一种测量肿瘤Topo-II水平的非侵入性检测方法有可能区分反应者和无反应者。为了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这一最终目标，我们基于ATP竞争性Topo-II抑制剂QAP1的结构设计、合成并评估了一组氟化化合物。化合物18和19b在体外试验中显示出对Topo-II的抑制作用，并在SK-BR-3和MCF-7细胞系中表现出中等程度的、依赖Topo-II水平的细胞毒性。基于这些结果，合成了这两种化合物的（18）F标记类似物，并作为PET探针评估其在携带SK-BR-3异种移植瘤的小鼠中对Topo-II过表达的成像能力。[（18）F]-18和[（18）F]-19b由其相应的受保护甲苯磺酰化衍生物通过氟化和随后的脱保护反应合成。小动物PET成像研究表明，这两种化合物均不聚集在肿瘤中，并且药代动力学较差，从血池清除非常迅速且会被代谢掉。从当前研究中获得的见解肯定会有助于设计和构建用于非侵入性描绘Topo-II表达的下一代PET试剂。
