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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• 作者：Verena Hugenberg ; Hans-J枚rg Breyholz ; Burkhard Riemann ; Sven Hermann ; Otmar Schober ; Michael Sch盲fers ; Umesh Gangadharmath ; Vani Mocharla ; Hartmuth Kolb ; Joseph Walsh ; Wei Zhang ; Klaus Kopka ; Stefan Wagner
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 24, 2012
• 年：2012
• 卷：55
• 期：10
• 页码：4714-4727
• 全文大小：610K
• 年卷期：v.55,no.10(May 24, 2012)
• ISSN：1520-4804

文摘

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., ¹⁸F) 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鈥?07 nM). Therefore, one promising fluorinated triazole-substituted hydroxamate (30b) was selected and resynthesised as its ¹⁸F-labeled version to yield the potential PET radioligand [¹⁸F]30b. The biodistribution behavior of this novel compound was investigated with small animal PET.