Synthesis and Preliminary Evaluation in Tumor Bearing Mice of New 18F-Labeled Arylsulfone Matrix Metalloproteinase Inhibitors as Tracers for Positron Emission Tomography

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• 作者：Francesca Casalini ; Lorenza Fugazza ; Giovanna Esposito ; Claudia Cabella ; Chiara Brioschi ; Alessia Cordaro ; Luca D鈥橝ngeli ; Antonietta Bartoli ; Azzurra M. Filannino ; Concetta V. Gringeri ; Dario L. Longo ; Valeria Muzio ; Elisa Nuti ; Elisabetta Orlandini ; Gianluca Figlia ; Angelo Quattrini ; Lorenzo Tei ; Giuseppe Digilio ; Armando Rossello ; Alessandro Maiocchi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2676-2689
• 全文大小：638K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

New fluorinated, arylsulfone-based matrix metalloproteinase (MMP) inhibitors containing carboxylate as the zinc binding group were synthesized as radiotracers for positron emission tomography. Inhibitors were characterized by K_i for MMP-2 in the nanomolar range and by a fair selectivity for MMP-2/9/12/13 over MMP-1/3/14. Two of these compounds were obtained in the ¹⁸F-radiolabeled form, with radiochemical purity and yield suitable for preliminary studies in mice xenografted with a human U-87 MG glioblastoma. Target density in xenografts was assessed by Western blot, yielding B_max/K_d = 14. The biodistribution of the tracer was dominated by liver uptake and hepatobiliary clearance. Tumor uptake of ¹⁸F-labeled MMP inhibitors was about 30% that of [¹⁸F]fluorodeoxyglucose. Accumulation of radioactivity within the tumor periphery colocalized with MMP-2 activity (evaluated by in situ zimography). However, specific tumor uptake accounted for only 18% of total uptake. The aspecific uptake was ascribed to the high binding affinity between the radiotracer and serum albumin.