title: Synthesis, radiosynthesis, in vitro and preliminary in vivo evaluation of biphenyl carboxylic and hydroxamic matrix metalloproteinase (MMP) inhibitors as potential tumor imaging agents.
abstract: Excess matrix degradation is one of the hallmarks of cancer and is an important factor in the process of tumor progression. It is implicated in invasion, metastasis, growth, angiogenesis and migration. Many characteristics of matrix metalloproteinases (MMPs) make them attractive therapeutic and diagnostic targets. MMP expression is upregulated at the tumor site, with localization of activity in the tumor or the surrounding stroma, providing a target for medical imaging techniques. Radioiodinated carboxylic and hydroxamic MMP inhibitors 2-(4'-[123I] iodo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid (9) and 2-(4'-[123I] iodo-biphenyl-4-sulfonylamino)-3-methyl-butyramide (11), their unlabelled standards and precursors were synthesized. Radioiodination was conducted by electrophilic aromatic substitution of the tributylstannyl precursors and resulted in radiochemical yields of 70+/-5% (n=6) and 60+/-5% (n=4), respectively. In vitro zymography and enzyme assays showed for both hydroxamic acid and carboxylic acid compounds a good inhibition activity and a high selectivity for MMP-2. In vivo biodistribution in NMRI mice showed no long-term accumulation in organs and the possibility to accumulate in the tumor in a later phase of this study.
authors.affiliation: Laboratory of Radiopharmacy, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium. ruth.oltenfreiter@ugent.be
authors.forename: Ruth
authors.initials: R
authors.lastname: Oltenfreiter
authors.forename: Ludovicus
authors.initials: L
authors.lastname: Staelens
authors.forename: Ulrik
authors.initials: U
authors.lastname: Hillaert
authors.forename: An
authors.initials: A
authors.lastname: Heremans
authors.forename: Agnes
authors.initials: A
authors.lastname: Noël
authors.forename: Francis
authors.initials: F
authors.lastname: Frankenne
authors.forename: Guido
authors.initials: G
authors.lastname: Slegers
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004341:Drug Evaluation; D005260:Female; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D002264:Carboxylic Acids; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors