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Novel Arginine-containing Macrocyclic MMP Inhibitors: Synthesis, 99mTc-labeling, and Evaluation.


ABSTRACT: 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 and 99mTc-labeled analog 99mTc-RYM1 for molecular imaging. RYM exhibited potent inhibition against a panel of recombinant human (rh) MMPs in vitro. RYM1 was efficiently labeled with 99mTcO4- to give 99mTc-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.

SUBMITTER: Ye Y 

PROVIDER: S-EPMC6076275 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Novel Arginine-containing Macrocyclic MMP Inhibitors: Synthesis, <sup>99m</sup>Tc-labeling, and Evaluation.

Ye Yunpeng Y   Toczek Jakub J   Gona Kiran K   Kim Hye-Yeong HY   Han Jinah J   Razavian Mahmoud M   Golestani Reza R   Zhang Jiasheng J   Wu Terence L TL   Ghosh Mousumi M   Jung Jae-Joon JJ   Sadeghi Mehran M MM  

Scientific reports 20180803 1


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 and <sup>99m</sup>Tc-labeled analog <sup>99m</sup>Tc-RYM1 for molecular imaging. RYM exhibited potent inhibition against a panel  ...[more]

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