Introduction of Peripheral Carboxylates to Decrease the Charge on Tm(3+) DOTAM-Alkyl Complexes: Implications for Detection Sensitivity and in Vivo Toxicity of PARACEST MRI Contrast Agents

J Med Chem. 2015 Aug 27;58(16):6516-32. doi: 10.1021/acs.jmedchem.5b00621. Epub 2015 Aug 6.

Abstract

A series of structurally modified Tm(3+) DOTAM-alkyl complexes as potential PARACEST MRI contrast agents has been synthesized with the aim to decrease the overall positive charge associated with these molecules and increase their biocompatibility. Two types of structural modification have been performed, an introduction of terminal carboxylate arms to the alkyl side chains and a conjugation of one of the alkyl side chains with aspartic acid. Detailed evaluation of the magnetic resonance imaging chemical exchange contrast associated with the structurally modified contrast agents has been performed. In contrast to the acutely toxic Tm(3+) DOTAM-alkyl complexes, the structurally modified compounds were found to be tolerated well during in vivo MRI studies in mice; however, only the aspartic acid modified chelates produced an amide proton-based PARACEST signal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspartic Acid / chemistry
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / pharmacology*
  • Contrast Media / chemical synthesis*
  • Contrast Media / toxicity*
  • Electron Spin Resonance Spectroscopy
  • Kidney / anatomy & histology
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Inbred C57BL
  • Organometallic Compounds / chemical synthesis*
  • Organometallic Compounds / toxicity*
  • Thulium / chemistry*

Substances

  • (1,4,7,10-tetrakis((N-(1H-imidazol-2-yl)carbamoyl)methyl)-1,4,7,10-tetraazacyclododecane)thulium(III)
  • Carboxylic Acids
  • Contrast Media
  • Organometallic Compounds
  • Aspartic Acid
  • Thulium