Inverse electron demand Diels–Alder (iEDDA)-initiated conjugation: a (high) potential click chemistry scheme

Abstract

Inverse electron demand Diels-Alder reactions (iEDDA) between 1,2,4,5-tetrazines and olefins have emerged into a state-of-the art concept for the conjugation of biomolecules. Now, this reaction is also increasingly being applied in polymer science and materials science. The orthogonality of this exciting reaction to other well-established click chemistry schemes, its high reaction speed and its biocompatibility are key features of iEDDA making it a powerful alternative to existing ligation chemistries. The intention of this tutorial review is to introduce the reader to the fundamentals of inverse electron demand Diels-Alder additions and to answer the question whether iEDDA chemistry is living up to the criteria for a ''click'' reaction and can serve as a basis for future applications in postsynthetic modification of materials. Key learning points(1) Electron-rich dienophiles and electron-poor dienes (e.g. tetrazines) react in an inverse electron demand Diels-Alder reaction (iEDDA).(2) iEDDA fulfils Sharpless' criteria for a ''click'' reaction while offering advantages over already established ''click'' chemistry schemes.

Site-specific conjugation allows modulation of click reaction stoichiometry for pretargeted SPECT imaging

“…11 These IEDDA reactions have second-order rate constants ranging from k 2  = 10 3 –10 6 M −1 s −1 , which are primarily driven by expulsion of N 2 and TCO strain relief following the cycloaddition 12,13 Furthermore, electron withdrawing substituents attached to the tetrazine confer increased reaction rates between the dienophile and diene. 14,15 Successful pretargeted in vivo nuclear imaging has been demonstrated in preclinical models using PET isotopes, including 11 C (t 1/2 20.3 minutes), 16,17 18 F (t 1/2 110 minutes) 18–20 and 64 Cu (t 1/2 12.7 hours), 4,21–24 as well as SPECT isotopes including 99m Tc (t 1/2 6 hours), 25–27 111 In (t 1/2 2.8 days) 28–30 and 177 Lu (t 1/2 6.7 days).…”

“…27,31–33 The recent success of IEDDA reactions for in vivo pretargeting and other chemical biology applications has been reviewed by several groups. 12,34–37 Most examples incorporate TCO on the slower clearing molecule followed by a fast clearing radiolabeled tetrazine tracer, but some groups have explored reversing the chemistry. 38,39 …”

18F-Labeling of Mannan for Inflammation Research with Positron Emission Tomography

“…13 As a prerequisite for PET, a suitable positronemitting pharmaceutical (PET tracer) needs to be administrated into patients prior to imaging. 18 F is the most often used positron emitter in clinical PET, due to its favorable physical properties (e.g., clean positron emitting process and low positron energy). Another favorable physical property of 18 F is its suitably long half-life (109.8 min), although 18 F is a shortlived radionuclide.…”

“…18 F is the most often used positron emitter in clinical PET, due to its favorable physical properties (e.g., clean positron emitting process and low positron energy). Another favorable physical property of 18 F is its suitably long half-life (109.8 min), although 18 F is a shortlived radionuclide. This enables multistep radiosynthesis feasible 14,15 and distribution to hospitals distanced from production sites possible.…”

“…16,17 Compound 1 (Figure 1) is an alkyne for conjugation of dextran-derived (or decorated) nanoparticles with copper-catalyzed 1,3-dipolar cycloaddition reactions. 16 In another work, tetrazine-bearing dextrans have been conjugated to 18 F-trans-cyclooctene ([ 18 F]TCO, Figure 1) based on inverse electron demand Diels−Alder (IEDDA) reaction. 17 IEDDA reaction has emerged as the fastest chemistry scheme, and tetrazine-trans-cyclooctene ligation has been widely applied in different technologies.…”