Synthesis of radioiodinated probes targeted toward matrix metalloproteinase-12. Issue 2 (15th January 2018)

• Record Type: Journal Article
• Authors: Hagimori, Masayori; Temma, Takashi; Kudo, Shinji; Sano, Kohei; Kondo, Naoya; Mukai, Takahiro
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 2(2018)
• Page Start: 193
• Page End: 195
• Publication Date: 2018-01-15
• Subjects: MMP-12 -- COPD -- Radioiodine -- Dibenzofuran -- Carbamate; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.11.027
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Matrix metalloproteinase-12 (MMP-12, macrophage elastase) is a member of the MMP family that is responsible for the degradation of extracellular matrix, and is associated with the inflammatory process of chronic obstructive pulmonary disease (COPD). COPD, characterized by progressive and irreversible airflow obstruction, is recently a major cause of mortality and morbidity worldwide. Herein, to develop radioiodinated probes for the early diagnosis of COPD, we designed and synthesized novel MMP-12-targeted dibenzofuran compounds (1 –3 ) with a variety of linker structures (carbamate, amide, and sulfonamide). In competitive enzyme activity assays, it was revealed that the linker structures significantly affected the inhibitory activity against and selectivity for MMP-12. Compound1, with carbamate linker, demonstrated potent MMP-12 inhibitory activity (IC50 = 8.5 nM) compared to compound2, with amide linker, and compound3, with sulfonamide linker. Using bromo-substituted carbamate13 as a radioiodination precursor, [ 125 I]1 was successfully prepared to high radiochemical purity (over 98%) and good specific radioactivity (4.1 GBq/μmol). These results suggest that radioiodinated compound1 is potent as a novel MMP-12-targeted probe.