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Sci Rep. 2016 Dec 5;6:38345. doi: 10.1038/srep38345.

Optical imaging of MMP-12 active form in inflammation and aneurysm.

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Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine and Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT USA.
Veterans Affairs Connecticut Healthcare System, West Haven, CT USA.
Commissariat à l'Energie Atomique, iBiTec-S, Service d'Ingénierie Moléculaire de Protéines, CE-Saclay, 91191 Gif -sur-Yvette cedex, France.
Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis, Zografou, 15771, Athens, Greece.


Matrix metalloproteinase (MMP)-12 plays a key role in the development of aneurysm. Like other members of MMP family, MMP-12 is produced as a proenzyme, mainly by macrophages, and undergoes proteolytic activation to generate an active form. Accordingly, molecular imaging of the MMP-12 active form can inform of the pathogenic process in aneurysm. Here, we developed a novel family of fluorescent probes based on a selective MMP-12 inhibitor, RXP470.1 to target the active form of MMP-12. These probes were stable in complex media and retained the high affinity and selectivity of RXP470.1 for MMP-12. Amongst these, probe 3 containing a zwitterionic fluorophore, ZW800-1, combined a favorable affinity profile toward MMP-12 and faster blood clearance. In vivo binding of probe 3 was observed in murine models of sterile inflammation and carotid aneurysm. Binding specificity was demonstrated using a non-binding homolog. Co-immunostaining localized MMP-12 probe binding to MMP-12 positive areas and F4/80 positive macrophages in aneurysm. In conclusion, the active form of MMP-12 can be detected by optical imaging using RXP470.1-based probes. This is a valuable adjunct for pathophysiology research, drug development, and potentially clinical applications.

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