Wang,MengzheSvatunek,DennisRohlfing,KatarinaLiu,YuWang,HuiGiglio,BenYuan,HongWu,ZhanghongLi,ZiboFox,Joseph2017-07-132017-07-132017 Ivysp4/12/16Wang, 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.147421838-7640http://udspace.udel.edu/handle/19716/21545Publisher's PDFThe 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.EnglishCC BY-NC 4.0Article10.7150/thno.14742