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

• Published in: Journal of medicinal chemistry Vol. 56; no. 6; pp. 2676 - 2689
• Main Authors: Casalini, Francesca, Fugazza, Lorenza, Esposito, Giovanna, Cabella, Claudia, Brioschi, Chiara, Cordaro, Alessia, D'Angeli, Luca, Bartoli, Antonietta, Filannino, Azzurra M., Gringeri, Concetta V., Longo, Dario L., Muzio, Valeria, Nuti, Elisa, Orlandini, Elisabetta, Figlia, Gianluca, Quattrini, Angelo, Tei, Lorenzo, Digilio, Giuseppe, Rossello, Armando, Maiocchi, Alessandro
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 28.03.2013
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; VITRO; DESIGN; IN-VIVO; BIOLOGICAL EVALUATION; CANCER; EXPRESSION; BINDING; LABELED MMP INHIBITOR; PET; PROBES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4001743

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 F-18-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 F-18-labeled MMP inhibitors was about 30% that of [F-18]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.