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Updated: Feb 4, 2026
Non-invasive In Vivo Fluorescence Optical Imaging of Inflammatory MMP Activity Using an Activatable Fluorescent Imaging Agent
Published on: May 8, 2017
New in Vivo Compatible Matrix Metalloproteinase (MMP)-2 and MMP-9 Inhibitors
Bernd Beutel1,2, Jian Song3,2, Christian Paul Konken1,2
1Organic Chemistry Institute , University of Münster , Corrensstraße 40 , 48149 Münster , Germany.
Abstract:
Matrix metalloproteinases (MMPs) are emerging as pivotal fine-tuners of cell function in tissue homeostasis and in various pathologies, in particular inflammation. In vivo monitoring of the activity of specific MMPs, therefore, provides high potential for assessing disease progression and tissue function, and manipulation of MMP activity in tissues and whole organisms may further provide a mode of controlling pathological processes. We describe here the synthesis of novel fluorinated and nonfluorinated analogues of a secondary sulfonamide-based lead structure, compound 2, and test their efficacy as in vivo inhibitors and tracers of the gelatinases, MMP-2 and MMP-9. Using a murine neuroinflammatory model, we show that compound 2 is a highly effective in vivo inhibitor of both MMP-2 and MMP-9 activity with little or no adverse effects even after long-term daily oral administration. A fluorescein-labeled derivative compound 17 shows direct binding to activated gelatinases surrounding inflammatory cuffs in the neuroinflammation model and to pancreatic β-cells in the islets of Langerhans, colocalizing with MMP-2 and MMP-9 activity as detected using in situ zymography techniques. These results demonstrate that compound 2 derivatives have potential as in vivo imaging tools and for future development for specific MMP-2 versus MMP-9 probes. Our chemical modifications mainly target the residues directed toward the S1' and S2' pockets and, thereby, provide new information on the structure-activity relationships of this inhibitor type.
Insights
Novel compounds effectively inhibit and image matrix metalloproteinases (MMPs), specifically MMP-2 and MMP-9, in a neuroinflammation model. These MMP inhibitors show potential for disease monitoring and therapeutic strategies.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Matrix metalloproteinases (MMPs) regulate tissue homeostasis and are implicated in inflammatory diseases.
- In vivo monitoring of MMP activity is crucial for assessing disease progression and tissue function.
- Targeting MMPs offers potential therapeutic strategies for pathological processes.
Purpose of the Study:
- To synthesize and evaluate novel fluorinated and nonfluorinated analogues of a secondary sulfonamide lead structure (compound 2) as inhibitors and tracers for MMP-2 and MMP-9.
- To assess the in vivo efficacy and safety of compound 2 in a murine neuroinflammatory model.
- To investigate the potential of a fluorescein-labeled derivative (compound 17) for imaging MMP activity in vivo.
Main Methods:
- Synthesis of novel secondary sulfonamide-based MMP inhibitors and tracers.
- In vivo efficacy testing in a murine neuroinflammatory model.
- In situ zymography and fluorescence imaging to detect MMP activity and compound binding.
Main Results:
- Compound 2 demonstrated effective in vivo inhibition of MMP-2 and MMP-9 activity with minimal adverse effects during long-term administration.
- A fluorescein-labeled derivative (compound 17) specifically bound to activated gelatinases in inflammatory cuffs and pancreatic β-cells.
- Compound 17 colocalized with MMP-2 and MMP-9 activity, confirming its utility as an imaging tool.
Conclusions:
- Compound 2 derivatives are promising as in vivo imaging agents for MMPs.
- These compounds hold potential for future development into specific MMP-2 or MMP-9 probes.
- Structure-activity relationship studies provide insights into inhibitor design targeting S1' and S2' pockets.
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