Application of metal-free triazole formation in the synthesis of cyclic RGD-DTPA conjugates.
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-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-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 alpha(v)beta(3) (IC(50)=192 nM) and favorable pharmacokinetics.
van Berkel
Sander S
SS
Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, NL.
Dirks
A ' Ton ' J
A'
Meeuwissen
Silvie A
SA
Pingen
Dennis L L
DL
Boerman
Otto C
OC
Laverman
Peter
P
van Delft
Floris L
FL
Cornelissen
Jeroen J L M
JJ
Rutjes
Floris P J T
FP
D000595:Amino Acid Sequence; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008670:Metals / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D004369:Pentetic Acid / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013194:Staining and Labeling; D014230:Triazoles / Q000737:chemistry*
D039302:Integrin alphaVbeta3; D008670:Metals; D009842:Oligopeptides; D010456:Peptides, Cyclic; D014230:Triazoles; C047981:arginyl-glycyl-aspartic acid; D004369:Pentetic Acid