Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario K1N 9B4, Canada.
University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
J Med Chem. 2023 May 25;66(10):6682-6696. doi: 10.1021/acs.jmedchem.2c02107. Epub 2023 May 9.
Matrix metalloproteinase-13 (MMP-13) plays a critical role in the progression of unstable atherosclerosis. A series of highly potent and selective MMP-13 inhibitors were synthesized around a quinazoline-2-carboxamide scaffold to facilitate radiolabeling with fluorine-18 or carbon-11 positron-emitting nuclides and visualization of atherosclerotic plaques. enzyme inhibition assays identified three compounds as promising radiotracer candidates. Efficient automated radiosyntheses provided , , and and enabled pharmacokinetic characterization in atherosclerotic mice. The radiotracers displayed substantial differences in their distribution and excretion. Most favorably for vascular imaging, exhibited low uptake in metabolic organs with minimal retention of myocardial radioactivity, substantial renal clearance, and high metabolic stability in plasma. aortic autoradiography and competition studies revealed that specifically binds to MMP-13 within atherosclerotic plaques and localizes to lipid-rich regions. This study demonstrates the utility of the quinazoline-2-carboxamide scaffold for MMP-13 selective positron emission tomography (PET) radiotracer development and identifies for imaging atherosclerosis.
基质金属蛋白酶-13（MMP-13）在不稳定型动脉粥样硬化的进展中起着关键作用。围绕喹唑啉-2-甲酰胺支架合成了一系列高活性和选择性的 MMP-13 抑制剂，以促进氟-18 或碳-11 正电子发射核素的放射性标记和动脉粥样硬化斑块的可视化。酶抑制测定鉴定出三种化合物作为有前途的示踪候选物。高效的自动化放射合成提供了 、 、 和 ，并能够在动脉粥样硬化小鼠中进行药代动力学特征描述。这些示踪剂在其分布和排泄方面表现出显著差异。最有利于血管成像的是 ，其在代谢器官中的摄取量低，心肌放射性滞留最小，肾脏清除率高，血浆代谢稳定性高。主动脉 Autoradiography 和竞争研究表明 特异性结合动脉粥样硬化斑块内的 MMP-13，并定位于富含脂质的区域。这项研究证明了喹唑啉-2-甲酰胺支架在 MMP-13 选择性正电子发射断层扫描（PET）示踪剂开发中的实用性，并确定 用于动脉粥样硬化成像。
