Design, synthesis, and evaluation of 1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid derived, redox-sensitive contrast agents for magnetic resonance imaging

Natarajan Raghunand, Gerald P. Guntle, Vijay Gokhale, Gary S. Nichol, Eugene A. Mash, Bhumasamudram Jagadish

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

The design and synthesis of three 1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid (DO3A) derivatives bearing linkers with terminal thiol groups and a preliminary evaluation of their potential for use in assembling redox-sensitive magnetic resonance imaging contrast agents are reported. The linkers were selected on the basis of computational docking with a crystal structure of human serum albumin (HSA). Gd(III)-DO3A and Eu(III)-DO3A complexes were synthesized, and the structure of one complex was established by X-ray crystallographic analysis. The binding to HSA of a Gd(III)-DO3A complex bearing a thiol-terminated 3,6-dioxanonyl chain was competitively inhibited by homocysteine and by the corresponding Eu chelate. Binding to HSA was abolished when the terminal thiol group of this complex was absent. The longitudinal water-proton relaxivities (r1) of the three Gd(III)-DO3A complexes and of two Gd(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexes were measured in saline at 7 T. The DO3A complexes exhibited smaller r1 values, in both bound and free states, than the DOTA complexes.

Original languageEnglish (US)
Pages (from-to)6747-6757
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number18
DOIs
StatePublished - Sep 23 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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