Department of Nuclear Medicine, University of Münster, Germany.
ChemMedChem. 2010 May 3;5(5):777-89. doi: 10.1002/cmdc.201000013.
Matrix metalloproteinases (MMPs) are zinc- and calcium-dependent endopeptidases. Representing a subfamily of the metzincin superfamily, MMPs are involved in the proteolytic degradation of components of the extracellular matrix. Unregulated MMP expression, MMP dysregulation and locally increased MMP activity are common features of various diseases, such as cancer, atherosclerosis, stroke, arthritis, and others. Therefore, activated MMPs are suitable biological targets for the specific visualization of such pathologies, in particular by using radiolabeled MMP inhibitors (MMPIs). The aim of this work was to develop a radiofluorinated molecular probe for noninvasive in vivo imaging for the detection of up-regulated levels of activated MMPs in the living organism. Fluorinated MMPIs (26, 31 and 38) based on the pyrimidine-2,4,6-trione lead structure RO 28-2653 (1) were synthesized, and their MMP inhibition potency was evaluated in vitro. The radiosynthesis and the in vivo biodistribution of the first (18)F-labeled prototype, MMP-targeted tracer [(18)F]26, suitable for molecular imaging by means of positron emission tomography (PET) were realized.
基质金属蛋白酶（MMPs）是锌和钙离子依赖性内肽酶。作为金属蛋白酶家族的一个亚家族，MMPs 参与细胞外基质成分的蛋白水解降解。MMP 表达失调、MMP 失调和局部 MMP 活性增加是多种疾病（如癌症、动脉粥样硬化、中风、关节炎等）的共同特征。因此，激活的 MMP 是特定可视化此类病变的合适生物靶标，特别是通过使用放射性标记的 MMP 抑制剂（MMPI）。本工作旨在开发一种用于活体非侵入性体内成像的放射性氟代分子探针，用于检测活体内上调的激活型 MMP 水平。基于嘧啶-2,4,6-三酮先导结构 RO 28-2653（1）合成了氟代 MMPIs（26、31 和 38），并在体外评估了它们的 MMP 抑制效力。首次（18）F 标记原型物（18）F]26 的放射合成和体内生物分布得到了实现，该原型物是一种适合通过正电子发射断层扫描（PET）进行分子成像的 MMP 靶向示踪剂。
