Development of hypoxia-sensitive Gd 3+-based MRI contrast agents

Shimpei Iwaki, Kenjiro Hanaoka, Wen Piao, Toru Komatsu, Tasuku Ueno, Takuya Terai, Tetsuo Nagano

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

Hypoxia occurs in various diseases, including cancer, ischemia, and acute and chronic vascular diseases. Here we describe the design and synthesis of the first hypoxia-sensitive MRI contrast agents, SAGds. SAGds showed a pH-dependent r 1 relaxivity change associated with intramolecular chelation of the nitrogen atom of the sulfonamide moiety to the Gd 3+ center. There was a correlation between the pK a of the r 1 relaxivity change and the sum of the Hammett σ constants of substituents on the aromatic ring. Among the synthesized compounds, 4NO 22MeOSAGd was selectively reduced to the amine by rat liver microsomes under hypoxic conditions, resulting in a 1.8-fold increment of the r 1 relaxivity owing to the change in pK a of the arylsulfonamide moiety. This enhancement of the r 1 relaxivity could be clearly detected in T 1-weighted MR images. Thus, 4NO 22MeOSAGd is a 'smart' MRI contrast agent for the detection of hypoxia under physiological conditions.

Original languageEnglish
Pages (from-to)2798-2802
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number8
DOIs
Publication statusPublished - 2012 Apr 15
Externally publishedYes

Keywords

  • Gadolinium
  • Hypoxia
  • MRI contrast agent

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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