Preclinical evaluation of potential infection-imaging probe [68Ga]Ga-DOTA-K-A9 in sterile and infectious inflammation

Karin Michaelsen Nielsen, Nis Pedersen Jørgensen, Majbritt H Kyneb, Per Borghammer, Rikke Louise Meyer, Trine R. Thomsen, Dirk Bender, Svend Borup Jensen, Ole Lerberg Nielsen, Aage Kristian Olsen Alstrup

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Abstract

The development of bacteria-specific infection radiotracers is of considerable interest to improve diagnostic accuracy and enabling therapy monitoring. The aim of this study was to determine if the previously reported radiolabelled 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA) conjugated peptide [ 68Ga]Ga-DOTA-K-A9 could detect a staphylococcal infection in vivo and distinguish it from aseptic inflammation. An optimized [ 68Ga]Ga-DOTA-K-A9 synthesis omitting the use of acetone was developed, yielding 93 ± 0.9% radiochemical purity. The in vivo infection binding specificity of [ 68Ga]Ga-DOTA-K-A9 was evaluated by micro positron emission tomography/magnetic resonance imaging of 15 mice with either subcutaneous Staphylococcus aureus infection or turpentine-induced inflammation and compared with 2-deoxy-2-[ 18F]fluoro-D-glucose ([ 18F]FDG). The scans showed that [ 68Ga]Ga-DOTA-K-A9 accumulated in all the infected mice at injected doses ≥3.6 MBq. However, the tracer was not found to be selective towards infection, since the [ 68Ga]Ga-DOTA-K-A9 also accumulated in mice with inflammation. In a concurrent in vitro binding evaluation performed with a 5-carboxytetramethylrhodamine (TAMRA) fluorescence analogue of the peptide, TAMRA-K-A9, the microscopy results suggested that TAMRA-K-A9 bound to an intracellular epitope and therefore preferentially targeted dead bacteria. Thus, the [ 68Ga]Ga-DOTA-K-A9 uptake observed in vivo is presumably a combination of local hyperemia, vascular leakiness and/or binding to an epitope present in dead bacteria.

Original languageEnglish
JournalJournal of Labelled Compounds and Radiopharmaceuticals
Volume61
Issue10
Pages (from-to)780-795
Number of pages16
ISSN0362-4803
DOIs
Publication statusPublished - 23 May 2018

Keywords

  • PET
  • S aureus
  • [ Ga]Ga-DOTA-K-A9
  • bacterial infection
  • fluorescence
  • gallium-68
  • murine models

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