Modular Assembly of Multimodal Imaging Agents through an Inverse Electron Demand Diels-Alder Reaction

Bioconjug Chem. 2019 Mar 20;30(3):888-897. doi: 10.1021/acs.bioconjchem.9b00017. Epub 2019 Feb 18.

Abstract

The combination of two imaging probes on the same biomolecule gives access to targeted bimodal imaging agents that can provide more accurate diagnosis, complementary information, or that may be used in different applications, such as nuclear imaging and fluorescence guided surgery. In this study, we demonstrate that dichlorotetrazine, a small, commercially available compound, can be used as a modular platform to easily assemble various imaging probes. Doubly labeled tetrazines can then be conjugated to a protein through a biorthogonal IEDDA reaction. A series of difunctionalized tetrazine compounds containing various chelating agents and fluorescent dyes was synthesized. As a proof of concept, one of these bimodal probes was conjugated to trastuzumab, previously modified with a constrained alkyne group, and the resulting dual-labeled antibody was evaluated in a mouse model, bearing a HER2-positive tumor. A significant uptake into tumor tissues was observed in vivo, by both SPECT-CT and fluorescence imaging, and confirmed ex vivo in biodistribution studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Contrast Media*
  • Cycloaddition Reaction*
  • Fluorescent Dyes / chemistry
  • Humans
  • Mice
  • Multimodal Imaging*
  • Proof of Concept Study
  • Trastuzumab / chemistry

Substances

  • Contrast Media
  • Fluorescent Dyes
  • Trastuzumab