title: Redox-active magnetic resonance imaging contrast agents: studies with thiol-bearing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid derivatives.
abstract: The synthesis and structure-activity relationships of a homologous series of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid gadolinium(III) complexes bearing thiol-terminated alkyl side chains from three to nine carbons in length are reported. The observed binding with human serum albumin (HSA) of the compounds having C-3 through C-7 side chain lengths was inhibited by homocysteine in a manner consistent with single-site binding. The observed binding with HSA of the compounds having C-8 and C-9 side chain lengths was only partly inhibited by homocysteine, consistent with multisite binding. The binding affinity of the C-7 compound could be related to the HSA oxidation state. 2D 1H-1H NMR TOCSY provided evidence of covalent binding of the europium analog of the C-6 compound to HSA-Cys34. The longitudinal water-proton MRI relaxivities of the gadolinium complexes at 7 T increased upon binding to HSA. On the basis of these results, the C-6 and C-7 compounds were identified as promising redox-sensitive MRI contrast agents.
authors.affiliation: Department of Chemistry and Biochemistry, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85721-0041, United States.
authors.forename: Bhumasamudram
authors.initials: B
authors.lastname: Jagadish
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Guntle
authors.forename: Dezheng
authors.initials: D
authors.lastname: Zhao
authors.forename: Vijay
authors.initials: V
authors.lastname: Gokhale
authors.forename: Tarik J
authors.initials: TJ
authors.lastname: Ozumerzifon
authors.forename: Ali M
authors.initials: AM
authors.lastname: Ahad
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Mash
authors.forename: Natarajan
authors.initials: N
authors.lastname: Raghunand
mesh_terms: D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology*; D003287:Contrast Media / Q000737:chemistry / Q000494:pharmacology*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: C578439:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid; D001372:Aza Compounds; D003287:Contrast Media; D006573:Heterocyclic Compounds, 1-Ring; D013438:Sulfhydryl Compounds