title: A new class of highly potent matrix metalloproteinase inhibitors based on triazole-substituted hydroxamates: (radio)synthesis and in vitro and first in vivo evaluation.
abstract: In vivo imaging of MMPs is of great (pre)clinical interest and can potentially be realized with modern three-dimensional and noninvasive in vivo molecular imaging techniques such as positron emission tomography (PET). Consequently, MMP inhibitors (MMPIs) radiolabeled with positron emitting nuclides (e.g., (18)F) represent a suitable tool for the visualization of activated MMPs with PET. On the basis of our previous work and results regarding radiolabeled and unlabeled derivatives of the nonselective MMPIs, we discovered a new class of fluorinated MMPIs with a triazole-substituted hydroxamate substructure. These novel MMPIs are characterized by an increased hydrophilicity compared with the lead structures and excellent MMP inhibition potencies for MMP-2, MMP-8, MMP-9, and MMP-13 (IC(50) = 0.006-107 nM). Therefore, one promising fluorinated triazole-substituted hydroxamate (30b) was selected and resynthesised as its (18)F-labeled version to yield the potential PET radioligand [(18)F]30b. The biodistribution behavior of this novel compound was investigated with small animal PET.
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster , Albert-Schweitzer-Campus 1, Building A1, D-48149 Münster, Germany. hugenber@uni-muenster.de
authors.forename: Verena
authors.initials: V
authors.lastname: Hugenberg
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Breyholz
authors.forename: Burkhard
authors.initials: B
authors.lastname: Riemann
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: Umesh
authors.initials: U
authors.lastname: Gangadharmath
authors.forename: Vani
authors.initials: V
authors.lastname: Mocharla
authors.forename: Hartmuth
authors.initials: H
authors.lastname: Kolb
authors.forename: Joseph
authors.initials: J
authors.lastname: Walsh
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
mesh_terms: D000818:Animals; D004355:Drug Stability; D057075:Enzyme Assays; D005462:Fluorine Radioisotopes; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: C574763:2-(N-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methyl)-4-methoxyphenylsulfonamido)-N-hydroxy-3-methylbutanamide; D005462:Fluorine Radioisotopes; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D014230:Triazoles; D020782:Matrix Metalloproteinases