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Synthesis of radioiodinated probes targeted toward matrix metalloproteinase-12
Masayori Hagimori1, Takashi Temma2, Shinji Kudo3
1Kobe Pharmaceutical University, 4-19-1 Motoyamakita Machi, Higashinada-ku, Kobe 658-8558, Japan; Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
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. Compound 1, with carbamate linker, demonstrated potent MMP-12 inhibitory activity (IC50 = 8.5 nM) compared to compound 2, with amide linker, and compound 3, with sulfonamide linker. Using bromo-substituted carbamate 13 as a radioiodination precursor, [125I]1 was successfully prepared to high radiochemical purity (over 98%) and good specific radioactivity (4.1 GBq/μmol). These results suggest that radioiodinated compound 1 is potent as a novel MMP-12-targeted probe.
Insights
Researchers developed novel MMP-12 targeted compounds for early diagnosis of chronic obstructive pulmonary disease (COPD). Compound 1, featuring a carbamate linker, showed potent MMP-12 inhibition and was successfully radioiodinated for potential diagnostic imaging.
Area of Science:
- Medicinal Chemistry
- Radiopharmaceutical Chemistry
- Biochemistry
Background:
- Matrix metalloproteinase-12 (MMP-12) is implicated in the inflammatory processes of chronic obstructive pulmonary disease (COPD).
- COPD is a progressive lung disease with significant global mortality and morbidity.
- Early diagnosis of COPD is crucial for effective management.
Purpose of the Study:
- To design and synthesize novel MMP-12-targeted compounds for potential early diagnosis of COPD.
- To evaluate the impact of different linker structures on MMP-12 inhibitory activity and selectivity.
- To develop a radioiodinated probe for MMP-12 imaging.
Main Methods:
- Synthesis of dibenzofuran compounds with carbamate, amide, and sulfonamide linkers.
- Competitive enzyme activity assays to determine inhibitory activity (IC50) and selectivity.
- Radioiodination of a precursor compound and characterization of the radiolabeled probe.
Main Results:
- Compound 1 (carbamate linker) exhibited potent MMP-12 inhibition (IC50 = 8.5 nM), outperforming compounds with amide and sulfonamide linkers.
- Linker structure significantly influenced MMP-12 inhibitory activity and selectivity.
- [125I]Compound 1 was prepared with high radiochemical purity (>98%) and specific radioactivity (4.1 GBq/μmol).
Conclusions:
- Novel MMP-12-targeted dibenzofuran compounds were successfully synthesized.
- The carbamate linker in compound 1 confers potent MMP-12 inhibitory activity.
- Radioiodinated compound 1 shows promise as a novel diagnostic probe for MMP-12 related diseases like COPD.
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