Redox-active Magnetic Resonance Imaging Contrast Agents: Studies with Thiol-bearing 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetracetic Acid Derivatives

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• 作者：Bhumasamudram Jagadish ; Gerald P. Guntle ; Dezheng Zhao ; Vijay Gokhale ; Tarik J. Ozumerzifon ; Ali M. Ahad ; Eugene A. Mash ; Natarajan Raghunand
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10378-10386
• 全文大小：436K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

The synthesis and structure鈥揳ctivity 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鈥?sup>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.