Optimization of Artificial Siderophores as 68Ga-Complexed PET Tracers for In Vivo Imaging of Bacterial Infections

J Med Chem. 2021 Aug 26;64(16):12359-12378. doi: 10.1021/acs.jmedchem.1c01054. Epub 2021 Aug 9.

Abstract

The diagnosis of bacterial infections at deep body sites benefits from noninvasive imaging of molecular probes that can be traced by positron emission tomography (PET). We specifically labeled bacteria by targeting their iron transport system with artificial siderophores. The cyclen-based probes contain different binding sites for iron and the PET nuclide gallium-68. A panel of 11 siderophores with different iron coordination numbers and geometries was synthesized in up to 8 steps, and candidates with the best siderophore potential were selected by a growth recovery assay. The probes [68Ga]7 and [68Ga]15 were found to be suitable for PET imaging based on their radiochemical yield, radiochemical purity, and complex stability in vitro and in vivo. Both showed significant uptake in mice infected with Escherichia coli and were able to discern infection from lipopolysaccharide-triggered, sterile inflammation. The study qualifies cyclen-based artificial siderophores as readily accessible scaffolds for the in vivo imaging of bacteria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cyclams / chemical synthesis
  • Cyclams / chemistry*
  • Cyclams / pharmacokinetics
  • Cyclams / toxicity
  • Escherichia coli
  • Escherichia coli Infections / diagnostic imaging*
  • Gallium Radioisotopes / chemistry
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscles / microbiology
  • Positron-Emission Tomography
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / chemistry*
  • Radiopharmaceuticals / pharmacokinetics
  • Radiopharmaceuticals / toxicity
  • Siderophores / chemical synthesis
  • Siderophores / chemistry*
  • Siderophores / pharmacokinetics
  • Siderophores / toxicity

Substances

  • Cyclams
  • Gallium Radioisotopes
  • Radiopharmaceuticals
  • Siderophores
  • Gallium-68