title: Novel Potent Proline-Based Metalloproteinase Inhibitors: Design, (Radio)Synthesis, and First in Vivo Evaluation as Radiotracers for Positron Emission Tomography.
abstract: As dysregulation of matrix metalloproteinase (MMP) activity is associated with a wide range of pathophysiological processes like cancer, atherosclerosis, and arthritis, MMPs represent a valuable target for the development of new therapeutics and diagnostic tools. We herein present the chiral pool syntheses, in vitro evaluation, and SAR studies of a series of d- and l-proline- as well as of (4R)-4-hydroxy-l-proline-derived MMP inhibitors possessing general formula 1. Some of the synthesized hydroxamic acids were found to be potent MMP inhibitors with IC50values in the nanomolar range, also demonstrating no off-target effects toward the other tested Zn2+-dependent metalloproteases (ADAMs and meprins). Utilizing the structure of the (2S,4S)-configured 4-hydroxyproline derivative 4, a selective picomolar inhibitor of MMP-13, the radiolabeled counterpart [18F]4 was successfully synthesized. The radiotracer's biodistribution in mice as well as its serum stability were evaluated for assessing its potential use as a MMP-13 targeting PET imaging agent.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster , Corrensstraße 48, 48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster , 48149 Münster, Germany.
authors.forename: Dmitrii V
authors.initials: DV
authors.lastname: Kalinin
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster , Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster , Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Riemann
authors.affiliation: Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster , 48149 Münster, Germany.|European Institute for Molecular Imaging, University of Münster , Waldeyerstraße 15, 48149 Münster, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.affiliation: Biochemical Institute, Christian-Albrechts-University Kiel , 24098 Kiel, Germany.
authors.forename: Frederike
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: Biochemical Institute, Christian-Albrechts-University Kiel , 24098 Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
authors.affiliation: Biochemical Institute, Christian-Albrechts-University Kiel , 24098 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster , 48149 Münster, Germany.|European Institute for Molecular Imaging, University of Münster , Waldeyerstraße 15, 48149 Münster, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster , Corrensstraße 48, 48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster , 48149 Münster, Germany.|German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel , 38124 Braunschweig, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Holl
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006801:Humans; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods*; D011392:Proline / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011849:Radioactive Tracers; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D011849:Radioactive Tracers; D011392:Proline; D045726:Metalloproteases