Synthesis and preliminary evaluation in tumor bearing mice of new 18F-labeled arylsulfone matrix metalloproteinase inhibitors as tracers for positron emission tomography

Francesca Casalini, Lorenza Fugazza, Giovanna Esposito, Claudia Cabella, Chiara Brioschi, Alessia Cordaro, Luca D'Angeli, 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

Research output: Contribution to journalArticlepeer-review

Abstract

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 Ki 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/Kd = 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.

Original languageEnglish
Pages (from-to)2676-2689
Number of pages14
JournalJournal of Medicinal Chemistry
Volume56
Issue number6
DOIs
Publication statusPublished - Mar 28 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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