Conformationally Strained trans-Cyclooctene (sTCO) Enables the Rapid Construction of F-18-PET Probes via Tetrazine Ligation
| Author(s) | Wang,Mengzhe | |
| Author(s) | Svatunek,Dennis | |
| Author(s) | Rohlfing,Katarina | |
| Author(s) | Liu,Yu | |
| Author(s) | Wang,Hui | |
| Author(s) | Giglio,Ben | |
| Author(s) | Yuan,Hong | |
| Author(s) | Wu,Zhanghong | |
| Author(s) | Li,Zibo | |
| Author(s) | Fox,Joseph | |
| Ordered Author | Mengzhe Wang, Dennis Svatunek, Katarina Rohlfing, Yu Liu, Hui Wang, Ben Giglio, Hong Yuan, Zhanghong Wu, Zibo Li, and Joseph Fox | |
| UD Author | Liu, Yun; Fox, Joseph M | |
| Date Accessioned | 2017-07-13T20:01:50Z | |
| Date Available | 2017-07-13T20:01:50Z | |
| Copyright Date | 2017 Ivyspring International Publisher | |
| Publication Date | 4/12/16 | |
| Description | Publisher's PDF | |
| 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 F-18-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 F-18 labeled sTCO derivative (F-18-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 degrees 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 F-18-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 F-18-sTCO should serve as a powerful and general platform for the rapid construction of peptide or protein derived PET agents. | |
| Department | University of Delaware, Department of Chemistry and Biochemistry | |
| Citation | Wang, M., Svatunek, D., Rohlfing, K., Liu, Y., Wang, H., Giglio, B., Fox, J. (2016). Conformationally strained trans-cyclooctene (sTCO) enables the rapid construction of F-18-PET probes via tetrazine ligation. Theranostics, 6(6), 887-895. doi:10.7150/thno.14742 | |
| DOI | 10.7150/thno.14742 | |
| ISSN | 1838-7640 | |
| URL | http://udspace.udel.edu/handle/19716/21545 | |
| Language | English | |
| Publisher | Ivyspring International Publisher | |
| dc.rights | CC BY-NC 4.0 | |
| dc.source | Theranostics | |
| dc.source.uri | http://www.thno.org/v06p0887.htm | |
| Title | Conformationally Strained trans-Cyclooctene (sTCO) Enables the Rapid Construction of F-18-PET Probes via Tetrazine Ligation | |
| Type | Article |
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