title: Radiofluorinated pyrimidine-2,4,6-triones as molecular probes for noninvasive MMP-targeted imaging.
abstract: Matrix metalloproteinases (MMPs) are zinc- and calcium-dependent endopeptidases. Representing a subfamily of the metzincin superfamily, MMPs are involved in the proteolytic degradation of components of the extracellular matrix. Unregulated MMP expression, MMP dysregulation and locally increased MMP activity are common features of various diseases, such as cancer, atherosclerosis, stroke, arthritis, and others. Therefore, activated MMPs are suitable biological targets for the specific visualization of such pathologies, in particular by using radiolabeled MMP inhibitors (MMPIs). The aim of this work was to develop a radiofluorinated molecular probe for noninvasive in vivo imaging for the detection of up-regulated levels of activated MMPs in the living organism. Fluorinated MMPIs (26, 31 and 38) based on the pyrimidine-2,4,6-trione lead structure RO 28-2653 (1) were synthesized, and their MMP inhibition potency was evaluated in vitro. The radiosynthesis and the in vivo biodistribution of the first (18)F-labeled prototype, MMP-targeted tracer [(18)F]26, suitable for molecular imaging by means of positron emission tomography (PET) were realized.
authors.affiliation: Department of Nuclear Medicine, University of Münster, Germany. breyholz@uni-muenster.de <breyholz@uni-muenster.de>
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Breyholz
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Andreas
authors.initials: A
authors.lastname: Faust
authors.forename: Burkhard
authors.initials: B
authors.lastname: Riemann
authors.forename: Carsten
authors.initials: C
authors.lastname: Höltke
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.forename: Otmar
authors.initials: O
authors.lastname: Schober
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
mesh_terms: D000818:Animals; D005462:Fluorine Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry*; D049268:Positron-Emission Tomography; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D061965:Matrix Metalloproteinase Inhibitors; D015335:Molecular Probes; D010879:Piperazines; D011480:Protease Inhibitors; D011743:Pyrimidines; C453902:Ro 28-2653; D020782:Matrix Metalloproteinases