The inverse electron demand Diels-Alder click reaction in radiochemistry

J Labelled Comp Radiopharm. 2014 Apr;57(4):285-90. doi: 10.1002/jlcr.3149. Epub 2013 Dec 18.


The inverse electron-demand Diels-Alder (IEDDA) cycloaddition between 1,2,4,5-tetrazines and strained alkene dienophiles is an emergent variety of catalyst-free 'click' chemistry that has the potential to have a transformational impact on the synthesis and development of radiopharmaceuticals. The ligation is selective, rapid, high-yielding, clean, and bioorthogonal and, since its advent in 2008, has been employed in a wide variety of chemical settings. In radiochemistry, the reaction has proven particularly useful with (18) F and has already been utilized to create a number of (18) F-labeled agents, including the PARP1-targeting small molecule (18) F-AZD2281, the αv β3 integrin-targeting peptide (18) F-RGD, and the GLP-1-targeting peptide (18) F-exendin. The inherent flexibility of the ligation has also been applied to the construction of radiometal-based probes, specifically the development of a modular strategy for the synthesis of radioimmunoconjugates that effectively eliminates variability in the construction of these agents. Further, the exceptional speed and biorthogonality of the reaction have made it especially promising in the realm of in vivo pretargeted imaging and therapy, and pretargeted imaging strategies based on the isotopes (111) In, (18) F, and (64) Cu have already proven capable of producing images with high tumor contrast and low levels of uptake in background, nontarget organs. Ultimately, the characteristics of inverse electron-demand Diels-Alder click chemistry make it almost uniquely well-suited for radiochemistry, and although the field is young, this ligation has the potential to make a tremendous impact on the synthesis, development, and study of novel radiopharmaceuticals.

Keywords: Diels-Alder; click chemistry; norbornene; pretargeting; radiochemistry; tetrazine; transcyclooctene.

Publication types

  • Review

MeSH terms

  • Animals
  • Cycloaddition Reaction / methods*
  • Electrons*
  • Humans
  • Radiochemistry / methods*
  • Radiopharmaceuticals / chemistry


  • Radiopharmaceuticals