A New Highly Reactive and Low Lipophilicity Fluorine-18 Labeled Tetrazine Derivative for Pretargeted PET Imaging

Outi Keinanen, Xiang-Guo Li, Naveen K. Chenna, Dave Lumen, Jennifer Ott, Carla F. M. Molthoff, Mirkka Sarparanta, Kerttuli Helariutta, Tapani Vuorinen, Albert D. Windhorst, Anu J. Airaksinen

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A new 18F-labeled tetrazine derivative was developed aiming at optimal radiochemistry, fast reaction kinetics in inverse electron-demand Diels–Alder cycloaddition (IEDDA), and favorable pharmacokinetics for in vivo bioorthogonal chemistry. The radiolabeling of the tetrazine was achieved in high yield, purity, and specific activity under mild reaction conditions via conjugation with 5-[18F]fluoro-5-deoxyribose, providing a glycosylated tetrazine derivative with low lipophilicity. The 18F-tetrazine showed fast reaction kinetics toward the most commonly used dienophiles in IEDDA reactions. It exhibited excellent chemical and enzymatic stability in mouse plasma and in phosphate-buffered saline (pH 7.41). Biodistribution in mice revealed favorable pharmacokinetics with major elimination via urinary excretion. The results indicate that the glycosylated 18F-labeled tetrazine is an excellent candidate for in vivo bioorthogonal chemistry applications in pretargeted PET imaging approaches.
Original languageEnglish
Pages (from-to)62-66
JournalAcs medicinal chemistry letters
Issue number1
Publication statusPublished - Jan 2016


  • Bioorthogonal chemistry
  • PET imaging
  • click chemistry
  • kinetics
  • tetrazine

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