title: Synthesis and preliminary evaluation in tumor bearing mice of new (18)F-labeled arylsulfone matrix metalloproteinase inhibitors as tracers for positron emission tomography.
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 (18)F-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 (18)F-labeled MMP inhibitors was about 30% that of [(18)F]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.
authors: Department of Science and Technological Innovation, Università del Piemonte Orientale "Amedeo Avogadro", Viale T. Michel 11, I-15121 Alessandria, Italy.
authors: Francesca
authors: F
authors: Casalini
authors: Lorenza
authors: L
authors: Fugazza
authors: Giovanna
authors: G
authors: Esposito
authors: Claudia
authors: C
authors: Cabella
authors: Chiara
authors: C
authors: Brioschi
authors: Alessia
authors: A
authors: Cordaro
authors: Luca
authors: L
authors: D'Angeli
authors: Antonietta
authors: A
authors: Bartoli
authors: Azzurra M
authors: AM
authors: Filannino
authors: Concetta V
authors: CV
authors: Gringeri
authors: Dario L
authors: DL
authors: Longo
authors: Valeria
authors: V
authors: Muzio
authors: Elisa
authors: E
authors: Nuti
authors: Elisabetta
authors: E
authors: Orlandini
authors: Gianluca
authors: G
authors: Figlia
authors: Angelo
authors: A
authors: Quattrini
authors: Lorenzo
authors: L
authors: Tei
authors: Giuseppe
authors: G
authors: Digilio
authors: Armando
authors: A
authors: Rossello
authors: Alessandro
authors: A
authors: Maiocchi
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D060326:Chemistry Techniques, Synthetic; D005462:Fluorine Radioisotopes; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000473:pathology*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011849:Radioactive Tracers; D011854:Radiochemistry; D012709:Serum Albumin / Q000378:metabolism; D013450:Sulfones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D005462:Fluorine Radioisotopes; D011480:Protease Inhibitors; D011849:Radioactive Tracers; D012709:Serum Albumin; D013450:Sulfones; D020782:Matrix Metalloproteinases