title: Optical imaging of MMP-12 active form in inflammation and aneurysm.
abstract: 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.
authors.affiliation: 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.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Razavian
authors.affiliation: Commissariat à l'Energie Atomique, iBiTec-S, Service d'Ingénierie Moléculaire de Protéines, CE-Saclay, 91191 Gif -sur-Yvette cedex, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bordenave
authors.affiliation: Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis, Zografou, 15771, Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Georgiadis
authors.affiliation: Commissariat à l'Energie Atomique, iBiTec-S, Service d'Ingénierie Moléculaire de Protéines, CE-Saclay, 91191 Gif -sur-Yvette cedex, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Beau
authors.affiliation: 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.
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Reza
authors.initials: R
authors.lastname: Golestani
authors.affiliation: 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.
authors.forename: Jakub
authors.initials: J
authors.lastname: Toczek
authors.affiliation: 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.
authors.forename: Jae-Joon
authors.initials: JJ
authors.lastname: Jung
authors.affiliation: 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.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Ye
authors.affiliation: 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.
authors.forename: Hye-Yeong
authors.initials: HY
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Jinah
authors.initials: J
authors.lastname: Han
authors.affiliation: Commissariat à l'Energie Atomique, iBiTec-S, Service d'Ingénierie Moléculaire de Protéines, CE-Saclay, 91191 Gif -sur-Yvette cedex, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
authors.affiliation: Commissariat à l'Energie Atomique, iBiTec-S, Service d'Ingénierie Moléculaire de Protéines, CE-Saclay, 91191 Gif -sur-Yvette cedex, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Devel
authors.affiliation: 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.
authors.forename: Mehran M
authors.initials: MM
authors.lastname: Sadeghi
mesh_terms: D000783:Aneurysm / Q000000981:diagnostic imaging* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D002339:Carotid Arteries / Q000000981:diagnostic imaging* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007249:Inflammation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D061848:Optical Imaging / Q000379:methods*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000378:metabolism; D013451:Sulfonic Acids / Q000737:chemistry / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D005456:Fluorescent Dyes; D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D000644:Quaternary Ammonium Compounds; C557203:RXP470.1 peptide; D013451:Sulfonic Acids; C562069:ZW800-1 compound; C036763:monocyte-macrophage differentiation antigen; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12