TY - JOUR

T1 - Synergistic Experimental and Computational Investigation of the Bioorthogonal Reactivity of Substituted Aryltetrazines

AU - Battisti, Umberto M.

AU - García-Vázquez, Rocío

AU - Svatunek, Dennis

AU - Herrmann, Barbara

AU - Löffler, Andreas

AU - Mikula, Hannes

AU - Herth, Matthias Manfred

N1 - Funding Information: This project has received funding from the European Union?s EU Framework Program for Research and Innovation Horizon 2020, under grant agreement no. 668532 and from the European Union?s Horizon 2020 research and innovation program under the Marie Sk?odowska-Curie grant agreement No. 813528. H.M. and M.M.H. have received funding from the European Union?s EU Framework Program for Research and Innovation Horizon 2020 (grant agreement no. 670261). The Lundbeck Foundation the Novo Nordisk Foundation, the Innovation Fund Denmark, and the Research Council for Independent Research (grant agreement no. 8022-00187B) are further acknowledged. Quantum chemical calculations were performed on the Vienna Scientific Cluster (Austria). The authors also acknowledge Xiaosong Xue (Nankai University) and Aneta Turlik (University of California Los Angeles) for fruitful discussions. Funding Information: This project has received funding from the European Unionʼs EU Framework Program for Research and Innovation Horizon 2020, under grant agreement no. 668532 and from the European Unionʼs Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 813528. H.M. and M.M.H. have received funding from the European Unionʼs EU Framework Program for Research and Innovation Horizon 2020 (grant agreement no. 670261). The Lundbeck Foundation, the Novo Nordisk Foundation, the Innovation Fund Denmark, and the Research Council for Independent Research (grant agreement no. 8022-00187B) are further acknowledged. Quantum chemical calculations were performed on the Vienna Scientific Cluster (Austria). The authors also acknowledge Xiaosong Xue (Nankai University) and Aneta Turlik (University of California, Los Angeles) for fruitful discussions. Publisher Copyright: © 2022 American Chemical Society. All rights reserved.

PY - 2022

Y1 - 2022

N2 - Tetrazines (Tz) have been applied as bioorthogonal agents for various biomedical applications, including pretargeted imaging approaches. In radioimmunoimaging, pretargeting increases the target-to-background ratio while simultaneously reducing the radiation burden. We have recently reported a strategy to directly 18F-label highly reactive tetrazines based on a 3-(3-fluorophenyl)-Tz core structure. Herein, we report a kinetic study on this versatile scaffold. A library of 40 different tetrazines was prepared, fully characterized, and investigated with an emphasis on second-order rate constants for the reaction with trans-cyclooctene (TCO). Our results reveal the effects of various substitution patterns and moreover demonstrate the importance of measuring reactivities in the solvent of interest, as click rates in different solvents do not necessarily correlate well. In particular, we report that tetrazines modified in the 2-position of the phenyl substituent show high intrinsic reactivity toward TCO, which is diminished in aqueous systems by unfavorable solvent effects. The obtained results enable the prediction of the bioorthogonal reactivity and thereby facilitate the development of the next generation of substituted aryltetrazines for in vivo applications.

AB - Tetrazines (Tz) have been applied as bioorthogonal agents for various biomedical applications, including pretargeted imaging approaches. In radioimmunoimaging, pretargeting increases the target-to-background ratio while simultaneously reducing the radiation burden. We have recently reported a strategy to directly 18F-label highly reactive tetrazines based on a 3-(3-fluorophenyl)-Tz core structure. Herein, we report a kinetic study on this versatile scaffold. A library of 40 different tetrazines was prepared, fully characterized, and investigated with an emphasis on second-order rate constants for the reaction with trans-cyclooctene (TCO). Our results reveal the effects of various substitution patterns and moreover demonstrate the importance of measuring reactivities in the solvent of interest, as click rates in different solvents do not necessarily correlate well. In particular, we report that tetrazines modified in the 2-position of the phenyl substituent show high intrinsic reactivity toward TCO, which is diminished in aqueous systems by unfavorable solvent effects. The obtained results enable the prediction of the bioorthogonal reactivity and thereby facilitate the development of the next generation of substituted aryltetrazines for in vivo applications.

U2 - 10.1021/acs.bioconjchem.2c00042

DO - 10.1021/acs.bioconjchem.2c00042

M3 - Journal article

C2 - 35290735

AN - SCOPUS:85127454394

VL - 33

SP - 608

EP - 624

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

SN - 1043-1802

IS - 4

ER -