Department of Nuclear Medicine, University Hospital Münster , Albert-Schweitzer-Campus 1, Building A1, D-48149 Münster, Germany.
J Med Chem. 2012 May 24;55(10):4714-27. doi: 10.1021/jm300199g. Epub 2012 May 16.
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., (18)F) 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 (IC(50) = 0.006-107 nM). Therefore, one promising fluorinated triazole-substituted hydroxamate (30b) was selected and resynthesised as its (18)F-labeled version to yield the potential PET radioligand [(18)F]30b. The biodistribution behavior of this novel compound was investigated with small animal PET.
体内 MMP 成像具有重要的（前）临床意义，并且可以通过现代的三维、非侵入性的体内分子成像技术来实现，例如正电子发射断层扫描（PET）。因此，用正电子发射核素（如（18）F）标记的基质金属蛋白酶抑制剂（MMPIs）代表了用 PET 可视化激活 MMP 的合适工具。基于我们之前关于放射性标记和非标记 MMPIs 衍生物的工作和结果，我们发现了一类具有三唑取代的羟肟酸结构的新型氟化 MMPIs。与先导结构相比，这些新型 MMPIs 的特点是亲水性增加，并且对 MMP-2、MMP-8、MMP-9 和 MMP-13 具有优异的 MMP 抑制活性（IC50=0.006-107 nM）。因此，选择了一种有前途的氟化三唑取代的羟肟酸（30b），并将其重新合成其（18）F 标记版本，得到潜在的 PET 放射性配体[（18）F]30b。用小动物 PET 研究了这种新型化合物的体内分布行为。
