Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine and Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut 06511, United States.
Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516, United States.
J Med Chem. 2020 Dec 10;63(23):15037-15049. doi: 10.1021/acs.jmedchem.0c01514. Epub 2020 Nov 18.
Macrophage elastase [matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence, MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis, and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CGA, CGA-1, and AGA) and the methodology to obtain MMP-12 selectivity from hydroxamate-based panMMP inhibitors. Also, we report two Tc-radiotracers, Tc-AGA-1 and Tc-AGA-2, derived from AGA. Tc-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to Tc-AGA-1. Based on this, Tc-AGA-2 was chosen as the lead tracer and tested in murine AAA. Tc-AGA-2 uptake detected by autoradiography was significantly higher in AAA compared to normal aortic regions. Specific binding of the tracer to MMP-12 was demonstrated through ex vivo competition. Accordingly, this study introduces a novel family of selective MMP-12 inhibitors and tracers, paving the way for further development of these agents as therapeutic and imaging agents.
巨噬细胞弹性蛋白酶[基质金属蛋白酶（MMP）-12]是腹主动脉瘤（AAA）中上调最明显的 MMP，因此，MMP-12 靶向成像可能预测 AAA 的进展和破裂风险。在这里，我们报告了三种新型基于羟肟酸的选择性 MMP-12 抑制剂（CGA、CGA-1 和 AGA）的设计、合成和评估，以及从基于羟肟酸的泛 MMP 抑制剂中获得 MMP-12 选择性的方法。此外，我们还报告了两种源自 AGA 的 Tc 放射性示踪剂 Tc-AGA-1 和 Tc-AGA-2。与 Tc-AGA-1 相比，Tc-AGA-2 在小鼠体内具有更快的血液清除率和更好的放射化学稳定性。基于此，选择 Tc-AGA-2 作为先导示踪剂，并在小鼠 AAA 中进行了测试。通过放射自显影检测到的 Tc-AGA-2 在 AAA 中的摄取明显高于正常主动脉区域。通过体外竞争证明了示踪剂与 MMP-12 的特异性结合。因此，本研究介绍了一类新型的选择性 MMP-12 抑制剂和示踪剂，为这些药物作为治疗和成像剂的进一步开发铺平了道路。
