title: Inverse 1,2,3-triazole-1-yl-ethyl substituted hydroxamates as highly potent matrix metalloproteinase inhibitors: (radio)synthesis, in vitro and first in vivo evaluation.
abstract: Noninvasive imaging and quantification of matrix metalloproteinase (MMP) activity in vivo are of great (pre)clinical interest. This can potentially be realized by using radiolabeled MMP inhibitors (MMPIs) as positron emission tomography (PET) imaging agents. Triazole-substituted MMPIs, discovered by our group, are highly potent inhibitors of MMP-2, -8, -9, and -13. The triazole ring and its position contribute significantly to the potency of the MMP inhibitor. To evaluate structure-activity relationships (SARs) of the initially discovered triazole-substituted MMPIs, an additional CH2-group between the backbone of the molecule and the triazole core was inserted, and the triazole ring was "inversed" by switching the alkyne and azide groups. Similar to the original triazole-substituted hydroxamates, the inverse triazole MMPIs are excellent inhibitors with promising in vivo properties. Pharmacokinetic properties and metabolic stability of an (18)F-labeled candidate in mice were investigated.
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster , Albert-Schweitzer-Campus 1, Building A1, D-48149 Münster, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Hugenberg
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: Katrin
authors.initials: K
authors.lastname: Szardenings
authors.forename: Artem
authors.initials: A
authors.lastname: Lebedev
authors.forename: Umesh
authors.initials: U
authors.lastname: Gangadharmath
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; D004353:Drug Evaluation, Preclinical; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D020782:Matrix Metalloproteinases / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014018:Tissue Distribution; D014230:Triazoles / Q000737:chemistry*
chemical_list: D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D014230:Triazoles; D020782:Matrix Metalloproteinases