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 Bmax/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.
|Autori interni:||NUTI, ELISA|
|Autori:||Casalini F; Fugazza L; Esposito G; Cabella C; Brioschi C; Cordaro A; D’Angeli L; Bartoli A; Filannino AM; Gringeri CV; Longo DL; Muzio V; Nuti E; Orlandini E; Figlia G; Quattrini A; Tei L; Digilio G; Rossello A; Maiocchi A|
|Titolo:||Synthesis and Preliminary Evaluation in Tumor Bearing Mice of New 18F‑Labeled Arylsulfone Matrix Metalloproteinase Inhibitors as Tracers for Positron Emission Tomography|
|Anno del prodotto:||2013|
|Digital Object Identifier (DOI):||10.1021/jm4001743|
|Appare nelle tipologie:||1.1 Articolo in rivista|