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Matrix metalloproteinases (MMPs) are emerging as pivotal fine-tuners of cell function in tissue homeostasis and in various pathologies, in particular inflammation. In vivomonitoring 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 vivoinhibitors and tracers of the gelatinases, MMP-2 and MMP-9. Using a murine neuroinflammatory model, we show that compound 2is a highly effective in vivoinhibitor 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 17shows 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 situzymography techniques. These results demonstrate that compound 2derivatives have potential as in vivoimaging 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.