title: Conformationally Strained trans-Cyclooctene (sTCO) Enables the Rapid Construction of (18)F-PET Probes via Tetrazine Ligation.
abstract: The bioorthogonal reaction between tetrazines and trans-cyclooctenes is a method for the rapid construction of F-18 probes for PET imaging. Described here is a second generation (18)F-labeling system based on a conformationally strained trans-cyclooctene (sTCO)-a dienophile that is approximately 2 orders of magnitude more reactive than conventional TCO dienophiles. Starting from a readily prepared tosylate precursor, an (18)F labeled sTCO derivative ((18)F-sTCO) could be synthesized in 29.3 +/- 5.1% isolated yield and with high specific activity. Tetrazine ligation was carried out with a cyclic RGD-conjugate of a diphenyl-s-tetrazine analogue (RGD-Tz) chosen from a diene class with an excellent combination of fast reactivity and stability both for the diene as well as the Diels-Alder adduct. For both the tetrazine and the sTCO, mini-PEG spacers were included to enhance solubility and improve the in vivo distribution profile of the resulting probe. Extremely fast reactivity (up to 2.86 x 10(5) M(-1)s(-1) at 25 °C in water) has been observed in kinetic studies in the reaction of sTCO with diphenyl-s-tetrazine derivatives. A kinetic study on sTCO diastereomers in 55:45 MeOH:water showed that the syn-diastereomer displayed slightly faster reactivity than the anti-diastereomer. An (18)F-sTCO conjugate with RGD-Tz demonstrated prominent and persistent tumor uptake in vivo with good tumor-to-background contrast. Unlike most radiolabeled RGD peptides, the tumor uptake of this PET agent increased from 5.3 +/- 0.2% ID/g at 1 h post injection (p.i.), to 8.9 +/- 0.5% ID/g at 4 h p.i., providing evidence for prolonged blood circulation. These findings suggest that tetrazine ligations employing (18)F-sTCO should serve as a powerful and general platform for the rapid construction of peptide or protein derived PET agents.
authors.affiliation: 1. Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States.
authors.forename: Mengzhe
authors.initials: M
authors.lastname: Wang
authors.affiliation: 2. Brown Laboratories, Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States.; 3. Institute of Applied Synthetic Chemistry, TU Wien, Vienna, 1060, Austria.
authors.forename: Dennis
authors.initials: D
authors.lastname: Svatunek
authors.affiliation: 2. Brown Laboratories, Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States.
authors.forename: Katarina
authors.initials: K
authors.lastname: Rohlfing
authors.affiliation: 2. Brown Laboratories, Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1. Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: 1. Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States.
authors.forename: Ben
authors.initials: B
authors.lastname: Giglio
authors.affiliation: 1. Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.affiliation: 1. Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States.
authors.forename: Zhanghong
authors.initials: Z
authors.lastname: Wu
authors.affiliation: 1. Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States.
authors.forename: Zibo
authors.initials: Z
authors.lastname: Li
authors.affiliation: 2. Brown Laboratories, Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Fox
mesh_terms: D000818:Animals; D034242:Cyclooctanes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers
chemical_list: D034242:Cyclooctanes; D005462:Fluorine Radioisotopes; D011849:Radioactive Tracers
keywords: 18F; RGD peptide.; bioorthogonal reaction; positron emission tomography (PET); strained trans-cyclooctene (sTCO)