title: Novel fluorinated derivatives of the broad-spectrum MMP inhibitors N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)- and (3-picolyl)-amino]-3-methyl-butanamide as potential tools for the molecular imaging of activated MMPs with PET.
abstract: An approach to the in vivo imaging of locally upregulated and activated matrix metalloproteinases (MMPs) found in many pathological processes is offered by positron emission tomography (PET). Hence, appropriate PET radioligands for MMP imaging are required. Here, we describe the syntheses of novel fluorinated MMP inhibitors (MMPIs) based on lead structures of the broad-spectrum inhibitors N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)-amino]-3-methyl-butanamide (CGS 25966) and N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](3-picolyl)-amino]-3-methyl-butanamide (CGS 27023A). Additionally, tailor-made precursor compounds for radiolabeling with the positron-emitter 18F were synthesized. All prepared hydroxamate target compounds showed high in vitro MMP inhibition potencies for MMP-2, MMP-8, MMP-9, and MMP-13. As a consequence, the promising fluorinated hydroxamic acid derivative 1f was resynthesized in its 18F-labeled version via two different procedures yielding the potential PET radioligand [18F]1f. As expected, the biodistribution behavior of this novel compound and that of the more hydrophilic variant [18F]1j, also developed by our group, indicates that there was no tissue specific accumulation in wild-type (WT) mice.
authors.affiliation: Department of Nuclear Medicine, University Hospital of the Westfälische Wilhelms-Universität Münster, Germany. stwagner@uni-muenster.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Breyholz
authors.forename: Marilyn P
authors.initials: MP
authors.lastname: Law
authors.forename: Andreas
authors.initials: A
authors.lastname: Faust
authors.forename: Carsten
authors.initials: C
authors.lastname: Höltke
authors.forename: Sandra
authors.initials: S
authors.lastname: Schröer
authors.forename: Günter
authors.initials: G
authors.lastname: Haufe
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
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; D004789:Enzyme Activation; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D008024:Ligands; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D049268:Positron-Emission Tomography; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; 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
chemical_list: C525471:2-(N-benzyl-4-(2-fluoroethoxy)phenylsulfonamido)-N-hydroxy-3-methylbutanamide; C097658:CGS 27023A; D005462:Fluorine Radioisotopes; D006877:Hydroxamic Acids; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; C490459:N-hydroxy-2-(((4'-methoxyphenyl)sulfonyl)benzylamino)-3-methylbutanamide; D011719:Pyrazines; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D020782:Matrix Metalloproteinases