Synthesis and Evaluation of Manganese(II)-Based Ethylenediaminetetraacetic Acid-Ethoxybenzyl Conjugate as a Highly Stable Hepatobiliary Magnetic Resonance Imaging Contrast Agent

Bioconjug Chem. 2018 Nov 21;29(11):3614-3625. doi: 10.1021/acs.bioconjchem.8b00560. Epub 2018 Nov 6.

Abstract

In this study, we designed and synthesized a highly stable manganese (Mn2+)-based hepatobiliary complex by tethering an ethoxybenzyl (EOB) moiety with an ethylenediaminetetraacetic acid (EDTA) coordination cage as an alternative to the well-established hepatobiliary gadolinium (Gd3+) chelates and evaluated its usage as a T1 hepatobiliary magnetic resonance imaging (MRI) contrast agent (CA). This new complex exhibits higher r1 relaxivity (2.3 mM-1 s-1) than clinically approved Mn2+-based hepatobiliary complex Mn-DPDP (1.6 mM-1 s-1) at 1.5 T. Mn-EDTA-EOB shows much higher kinetic inertness than that of clinically approved Gd3+-based hepatobiliary MRI CAs, such as Gd-DTPA-EOB and Gd-BOPTA. In addition, in vivo biodistribution and MRI enhancement patterns of this new Mn2+ chelate are comparable to those of Gd3+-based hepatobiliary MRI CAs. The diagnostic efficacy of the new complex was demonstrated by its enhanced tumor detection sensitivity in a liver cancer model using in vivo MRI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biliary Tract / diagnostic imaging*
  • Cell Line
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacokinetics
  • Contrast Media / chemical synthesis*
  • Contrast Media / chemistry
  • Edetic Acid / chemistry*
  • Edetic Acid / pharmacokinetics
  • Female
  • Gadolinium DTPA / chemistry
  • Heterografts
  • Humans
  • Hydrogen-Ion Concentration
  • Kinetics
  • Liver / diagnostic imaging*
  • Liver Neoplasms / diagnostic imaging
  • Liver Neoplasms / pathology
  • Magnetic Resonance Imaging / methods*
  • Male
  • Manganese / chemistry*
  • Mice
  • Molecular Docking Simulation
  • Proton Magnetic Resonance Spectroscopy
  • Spectrometry, Mass, Electrospray Ionization
  • Spectrometry, Mass, Fast Atom Bombardment

Substances

  • Chelating Agents
  • Contrast Media
  • Manganese
  • Edetic Acid
  • Gadolinium DTPA