title: Development of a (18) F-labeled tetrazine with favorable pharmacokinetics for bioorthogonal PET imaging.
abstract: A low-molecular-weight (18) F-labeled tetrazine derivative was developed as a highly versatile tool for bioorthogonal PET imaging. Prosthetic groups and undesired carrying of (18) F through additional steps were evaded by direct (18) F-fluorination of an appropriate tetrazine precursor. Reaction kinetics of the cycloaddition with trans-cyclooctenes were investigated by applying quantum chemical calculations and stopped-flow measurements in human plasma; the results indicated that the labeled tetrazine is suitable as a bioorthogonal probe for the imaging of dienophile-tagged (bio)molecules. In vitro and in vivo investigations revealed high stability and PET/MRI in mice showed fast homogeneous biodistribution of the (18) F-labeled tetrazine that also passes the blood-brain barrier. An in vivo click experiment confirmed the bioorthogonal behavior of this novel tetrazine probe. Due to favorable chemical and pharmacokinetic properties this bioorthogonal agent should find application in bioimaging and biomedical research.
authors.affiliation: Institut für Angewandte Synthesechemie, Technische Universität Wien (TUW) (Austria).
authors.forename: Christoph
authors.initials: C
authors.lastname: Denk
authors.forename: Dennis
authors.initials: D
authors.lastname: Svatunek
authors.forename: Thomas
authors.initials: T
authors.lastname: Filip
authors.forename: Thomas
authors.initials: T
authors.lastname: Wanek
authors.forename: Daniel
authors.initials: D
authors.lastname: Lumpi
authors.forename: Johannes
authors.initials: J
authors.lastname: Fröhlich
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuntner
authors.forename: Hannes
authors.initials: H
authors.lastname: Mikula
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis; D061565:Cycloaddition Reaction; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D007553:Isotope Labeling; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D001643:Bridged Bicyclo Compounds; D005462:Fluorine Radioisotopes; D006571:Heterocyclic Compounds; D019275:Radiopharmaceuticals
keywords: bioorthogonal chemistry; click chemistry; imaging agents; kinetics; tetrazines