Design, Synthesis, and Initial Evaluation of a High Affinity Positron Emission Tomography Probe for Imaging Matrix Metalloproteinases 2 and 9

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• 作者：Svetlana V. Selivanova ; Timo Stellfeld ; Tobias K. Heinrich ; Adrienne M眉ller ; Stefanie D. Kr盲mer ; P. August Schubiger ; Roger Schibli ; Simon M. Ametamey ; Bernhard Vos ; J枚rg Meding ; Marcus Bauser ; Joachim H眉tter ; Ludger M. Dinkelborg
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 27, 2013
• 年：2013
• 卷：56
• 期：12
• 页码：4912-4920
• 全文大小：463K
• 年卷期：v.56,no.12(June 27, 2013)
• ISSN：1520-4804

文摘

The activity of matrix metalloproteinases (MMPs) is elevated locally under many pathological conditions. Gelatinases MMP2 and MMP9 are of particular interest because of their implication in angiogenesis, cancer cell proliferation and metastasis, and atherosclerotic plaque rupture. The aim of this study was to identify and develop a selective gelatinase inhibitor for imaging active MMP2/MMP9 in vivo. We synthesized a series of N-sulfonylamino acid derivatives with low to high nanomolar inhibitory potencies. (R)-2-(4-(4-Fluorobenzamido)phenylsulfonamido)-3-(1H-indol-3-yl)propanoic acid (7) exhibited the best in vitro binding properties: MMP2 IC₅₀ = 1.8 nM, MMP9 IC₅₀ = 7.2 nM. Radiolabeling of 7 with no carrier added ¹⁸F-radioisotope was accomplished starting from iodonium salts as precursors. The radiochemical yield strongly depended on the iodonium counteranion (ClO₄^{鈥?/sup> > Br鈥?/sup> > TFA鈥?/sup> > tosylate). 18F-7 was obtained in up to 20% radiochemical yield (decay corrected), high radiochemical purity, and >90 GBq/渭mol specific radioactivity. The radiolabeled compound showed excellent stability in vitro and in mice in vivo.}