The tandem 1,3-dipolar cycloaddition-retro-Diels–Alder (tandem crDA) reaction is presented as a versatile method for metal-free chemoselective conjugation of a DTPA radiolabel to N-δ-azido-cyclo(-Arg-Gly-Asp-d-Phe-Orn-) via oxanorbornadiene derivatives. To this end, the behavior of several trifluoromethyl-substituted oxanorbornadiene derivatives in the 1,3-dipolar cycloaddition was studied and optimized to give a clean and efficient method for bio-orthogonal ligation in an aqueous environment. After radioisotope treatment, the resulting 111In-labeled c(RGD)-CF3-triazole-DTPA conjugate was subjected to preliminary biological evaluation and showed high affinity for αvβ3 (IC50=192 nM) and favorable pharmacokinetics.
van Berkel, S. S., Dirks, A. J., Meeuwissen, S. A., Pingen, D. L. L., Boerman, O. C., Laverman, P., ... Rutjes, F. P. J. T. (2008). Application of Metal-Free Triazole Formation in the Synthesis of Cyclic RGD–DTPA Conjugates. ChemBioChem, 9(11), 1805-1815. https://doi.org/10.1002/cbic.200800074