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

Umberto M Battisti, Rocío García-Vázquez, Dennis Svatunek, Barbara Herrmann, Andreas Löffler, Hannes Mikula, Matthias Manfred Herth*

*Corresponding author af dette arbejde

Abstract

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.

OriginalsprogEngelsk
TidsskriftBioconjugate Chemistry
Vol/bind33
Udgave nummer4
Sider (fra-til)608-624
Antal sider17
ISSN1043-1802
DOI
StatusUdgivet - 20 apr. 2022

Fingeraftryk

Dyk ned i forskningsemnerne om 'Synergistic Experimental and Computational Investigation of the Bioorthogonal Reactivity of Substituted Aryltetrazines'. Sammen danner de et unikt fingeraftryk.

Citationsformater