Application of metal-free triazole formation in the synthesis of cyclic RGD-DTPA conjugates

The tandem 1,3-dipolor cycloaddition-retro-Diels-Alder (tandem crDA) reaction is presented as a versatile method for metal-free chemoselective conjugation of a DTPA radiolabel to N-delta-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-dipolor 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 In-111-labeled c(RGD)-CF3-triozole-DTPA conjugate was subjected to preliminary biological evaluation and showed high affinity for alpha(v)beta(3), (IC50 = 192 nM) and favorable pharmacokinetics.