title: Tumor detection using 18F-labeled matrix metalloproteinase-2 inhibitor.
abstract: Matrix metalloproteinase-2 (MMP-2) is a key enzyme involved in tumor invasiveness. (2R)-2- [4-(6-[(18)F]Fluorohex-1-ynyl)-benzenesulfonylamino]-3-methylbutyric acid ([(18)F]SAV03), a new fluorine-18 labeled MMP-2 inhibitor developed for tumor imaging with PET, was biologically evaluated using in vivo tumor model. Enzymatic MMP-2 assay of SAV03 yielded an IC(50) value of 1.9 microM. Biodistribution study of [(18)F]SAV03 using Ehrlich tumor bearing mice showed that the uptake in tumor was higher than in other organs, except for the liver, small intestine, and bone. When [(18)F]SAV03M, a methyl ester of [(18)F]SAV03, was used as a prodrug, the uptake in liver at 30 min after injection decreased by half and that in tumor increased by 2.4 times, compared with [(18)F]SAV03. Radio-thin-layer chromatographic analysis of [(18)F]SAV03M metabolites revealed that administered [(18)F]SAV03M was easily converted to the parent drug in vivo and accumulated in tumor tissue. Thus, [(18)F]SAV03M is suitable as the prodrug of [(18)F]SAV03 with potent efficacy. Whole body autoradiography using [(18)F]SAV03M also indicated tumor-specific accumulation of radioactivity, while higher accumulations in bone and intestinal contents were observed. Our results suggest that [(18)F]SAV03M could be potentially suitable for tumor imaging with PET.
authors.affiliation: Institute of Development, Aging and Cancer and Graduate School of Pharmaceutical Scinces, Tohoku University, Sendai, Japan. shozo@idac.tohoku.ac.jp
authors.forename: Shozo
authors.initials: S
authors.lastname: Furumoto
authors.forename: Kyoka
authors.initials: K
authors.lastname: Takashima
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kubota
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ido
authors.forename: Ren
authors.initials: R
authors.lastname: Iwata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D001345:Autoradiography / Q000379:methods; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002286:Carcinoma, Ehrlich Tumor / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods; D014633:Valine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D014915:Whole-Body Counting
chemical_list: C478094:2-(4-(6-fluorohex-1-ynyl)benzenesulfonylamino)-3-methylbutyric acid; D014408:Biomarkers, Tumor; D061965:Matrix Metalloproteinase Inhibitors; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D020778:Matrix Metalloproteinase 2; D014633:Valine