A New Class of Highly Potent Matrix Metalloproteinase Inhibitors Based on Triazole-Substituted Hydroxamates: (Radio)Synthesis and in Vitro and First in Vivo Evaluation
A New Class of Highly Potent Matrix Metalloproteinase Inhibitors Based on Triazole-Substituted Hydroxamates: (Radio)Synthesis and in Vitro and First in Vivo Evaluation
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DOI：
10.1021/jm300199g
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发表时间：
2012-05-24
影响因子：
7.3
通讯作者：
Wagner, Stefan
中科院分区：
文献类型：
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作者：
Hugenberg, Verena;Breyholz, Hans-Joerg;Wagner, Stefan
MMPs的体内成像具有重要的（预）临床意义，可以通过现代三维和无创体内分子成像技术（如正电子发射断层扫描（PET））来实现。因此，用正电子发射核素（如F-18）进行放射性标记的MMP抑制剂（MMPIs）代表了用PET可视化活化MMP的合适工具。在我们之前关于非选择性MMPIs的放射性标记和未标记衍生物的工作和结果的基础上，我们发现了一类新的具有三唑取代羟基甲酸酯亚结构的氟化MMPIs。与铅结构相比，这些新型MMPIs具有更高的亲水性，并且对MMP-2、MMP-8、MMP-9和MMP-13具有良好的抑制作用（IC50 = 0.006-107 nM）。因此，我们选择了一种很有前途的氟化三唑取代羟基甲酸酯（30b），并将其重新合成为F-18标记的版本，从而得到潜在的PET放射性配体[F-18]30b。用小动物PET研究了该化合物的生物分布行为。
In vivo imaging of MMPs is of great (pre)clinical interest and can potentially be realized with modern three-dimensional and noninvasive in vivo molecular imaging techniques such as positron emission tomography (PET). Consequently, MMP inhibitors (MMPIs) radiolabeled with positron emitting nuclides (e.g., F-18) represent a suitable tool for the visualization of activated MMPs with PET. On the basis of our previous work and results regarding radiolabeled and unlabeled derivatives of the nonselective MMPIs, we discovered a new class of fluorinated MMPIs with a triazole-substituted hydroxamate substructure. These novel MMPIs are characterized by an increased hydrophilicity compared with the lead structures and excellent MMP inhibition potencies for MMP-2, MMP-8, MMP-9, and MMP-13 (IC50 = 0.006-107 nM). Therefore, one promising fluorinated triazole-substituted hydroxamate (30b) was selected and resynthesised as its F-18-labeled version to yield the potential PET radioligand [F-18]30b. The biodistribution behavior of this novel compound was investigated with small animal PET.