Redox-sensitive contrast agents for MRI based on reversible binding of thiols to serum albumin

Natarajan Raghunand, Bhumasamudram Jagadish, Theodore P Trouard, Jean Philippe Galons, Robert J. Gillies, Eugene A. Mash

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

DOTA-based complexes of gadolinium (Gd) bearing a thiol moiety on a propyl or hexyl arm were synthesized. It was hypothesized that these complexes would form reversible covalent linkages with human serum albumin (HSA), which contains a reactive thiol at cysteine-34. The binding constant of the hexyl complex to HSA was measured to be 64 mM-1 and decreased to 17, 6.1, and 3.6 mM-1 in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The binding constant of the propyl complex to HSA was significantly lower (5.0 mM-1) and decreased to 2.0, 1.5, and 0.87 mM-1 in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The longitudinal water-proton relativities of the hexyl and propyl complexes at 37°C and 4.7 T were 2.3 and 2.9 mM-1 s-1, respectively, in saline. The relaxivities of the HSA-bound forms of the hexyl and propyl complexes were calculated to be 5.3 and 4.5 mM-1 s-1, respectively. The in vivo pharmacokinetics of both thiol complexes were altered by a chase of homocysteine but not saline, while the washout of GdDTPA was unaffected by either chase. Such redox-sensitive reversible binding of Gd complexes to plasma albumin can be exploited for imaging tissue redox and the blood-pool by MRI.

Original languageEnglish (US)
Pages (from-to)1272-1280
Number of pages9
JournalMagnetic Resonance in Medicine
Volume55
Issue number6
DOIs
StatePublished - Jun 2006

Keywords

  • Albumin
  • Blood-pool
  • Gadolinium
  • Redox
  • Thiol

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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