Novel Arginine-containing Macrocyclic MMP Inhibitors: Synthesis, 99mTc-labeling, and Evaluation.
Novel Arginine-containing Macrocyclic MMP Inhibitors: Synthesis, 99mTc-labeling, and Evaluation.
复制标题
新型含精氨酸大环 MMP 抑制剂：合成、99mTc 标记和评估。
DOI：
10.1038/s41598-018-29941-2
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发表时间：
2018
影响因子：
4.6
通讯作者：
Sadeghi,MehranM
中科院分区：
文献类型：
--
作者：
Ye,Yunpeng;Toczek,Jakub;Gona,Kiran;Kim,Hye-Yeong;Han,Jinah;Razavian,Mahmoud;Golestani,Reza;Zhang,Jiasheng;Wu,TerenceL;Ghosh,Mousumi;Jung,Jae-Joon;Sadeghi,MehranM
基质金属蛋白酶（MMP）参与组织重塑。因此，MMP抑制剂和相关的放射性标记的类似物是许多疾病中MMP靶向成像和治疗的重要工具。本文报道了一种新的含精氨酸的大环异羟肟酸类似物RYM、其肼基烟酰胺偶联物RYM 1和99 mTc标记的类似物99 mTc-RYM 1的设计、合成和评价。RYM在体外对一组重组人（rh）MMPs表现出有效的抑制作用。用99 mTcO 4-有效标记RYM 1，得到高放化产率和高放化纯度的99 mTc-RYM 1。RYM 1及其降解的标记产物对rhMMP-12的抑制效力相似。此外，99 mTc-RYM 1表现出与肺特异性白细胞介素-13转基因小鼠的肺组织特异性结合，其中MMP活性与组织重塑和炎症一起增加。结果支持进一步开发这种新的水溶性含精氨酸的大环异羟肟酸MMP抑制剂用于靶向成像和治疗。
Matrix metalloproteinases (MMPs) are involved in tissue remodeling. Accordingly, MMP inhibitors and related radiolabeled analogs are important tools for MMP-targeted imaging and therapy in a number of diseases. Herein, we report design, synthesis, and evaluation of a new Arginine-containing macrocyclic hydroxamate analog, RYM, its hydrazinonicotinamide conjugate, RYM1 and99mTc-labeled analog99mTc-RYM1 for molecular imaging. RYM exhibited potent inhibition against a panel of recombinant human (rh) MMPsin vitro. RYM1 was efficiently labeled with99mTcO4−to give99mTc-RYM1 in a high radiochemical yield and high radiochemical purity. RYM1 and its decayed labeling product displayed similar inhibition potencies against rhMMP-12. Furthermore,99mTc-RYM1 exhibited specific binding with lung tissue from lung-specific interleukin-13 transgenic mice, in which MMP activity is increased in conjunction with tissue remodeling and inflammation. The results support further development of such new water-soluble Arginine-containing macrocyclic hydroxamate MMP inhibitors for targeted imaging and therapy.