cGMP-Compatible preparative scale synthesis of near-infrared fluorophores

Contrast Media Mol Imaging. Nov-Dec 2012;7(6):516-24. doi: 10.1002/cmmi.1484.

Abstract

Image-guided surgery using optical imaging requires the availability of large quantities of clinical-grade fluorophores. We describe the cGMP-compatible synthesis of the zwitterionic heptamethine indocyanine near-infrared fluorophore ZW800-1 at the 10 g scale (~1000 patient doses) using facile and efficient solvent purification, and without the need for column chromatography. ZW800-1 has >90% yield at the final step and >99% purity as measured by fluorescence and evaporative light scatter detection. We describe an analytical framework for qualifying impurities, as well as a detailed analysis of counterion identities. Finally, we report the unique in vivo properties of ZW800-1 in large animals approaching the size of humans, thus laying the foundation for rapid clinical translation of these methods.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic GMP / chemistry*
  • Female
  • Fluorescent Dyes / chemical synthesis*
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / pharmacokinetics
  • Male
  • Mice
  • Mice, Inbred ICR
  • Quaternary Ammonium Compounds / chemical synthesis*
  • Quaternary Ammonium Compounds / chemistry
  • Quaternary Ammonium Compounds / pharmacokinetics
  • Spectroscopy, Near-Infrared
  • Sulfonic Acids / chemical synthesis*
  • Sulfonic Acids / chemistry
  • Sulfonic Acids / pharmacokinetics
  • Swine

Substances

  • Fluorescent Dyes
  • Quaternary Ammonium Compounds
  • Sulfonic Acids
  • ZW800-1 compound
  • Cyclic GMP