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

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• 作者：Stefan Wagner ; Hans-Jö ; rg Breyholz ; Marilyn P. Law ; Andreas Faust ; Carsten Hö ; ltke ; Sandra Schrö ; er ; Gü ; nter Haufe ; Bodo Levkau ; Otmar Schober ; Michael Schä ; fers ; Klaus Kopka
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 15, 2007
• 年：2007
• 卷：50
• 期：23
• 页码：5752 - 5764
• 全文大小：227K
• 年卷期：v.50,no.23(November 15, 2007)
• ISSN：1520-4804

文摘

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, appropriatePET radioligands for MMP imaging are required. Here, we describe the syntheses of novel fluorinatedMMP 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-madeprecursor compounds for radiolabeling with the positron-emitter ¹⁸F were synthesized. All preparedhydroxamate 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 resynthesizedin its ¹⁸F-labeled version via two different procedures yielding the potential PET radioligand [¹⁸F]1f. Asexpected, 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.