Modular CuAAC-Based Synthesis of C-Functional Cyclam-Picolinate Chelators for Antibody Conjugation
Cédric Ollier, Dyhia Amrane, Guillaume Gabant, Nicolas Joubert, Caroline Denevault-Sabourin, Nathalie Le Bris, Raphaël Tripier
J. Org. Chem. 2026, 91, 14, 4842–4855, DOI: 10.1021/acs.joc.5c02275
Published 1 April 2026
 

A modular strategy was developed for the bifunctionalization of TE1PA, a cyclam-based copper chelator used in nuclear medicine, via Cu(I)-catalyzed Azide–Alkyne Cycloaddition (CuAAC) and thiol-maleimide chemistry, to enable site-selective bioconjugation. An alkyne-functionalized TE1PA derivative was synthesized in high yield using a Boc/Teoc-protected intermediate and was subsequently coupled to azido-PEG3-biotin and azido-PEGn-maleimide linkers (n = 3 or 6), affording triazole-linked conjugates in 50 to 82% overall yields. The maleimide-TE1PA derivatives were conjugated to trastuzumab via cysteine residues, yielding well-defined immunoconjugates with chelator-to-antibody ratios (CARs) ranging from 2.2 to 3.8 and satisfactory yields (59–78%). In contrast, analogous conjugates prepared from the conventional p-NH2–Bn-TE1PA using peptide coupling showed lower CARs (0.9–1.8) and lower isolated yields (7–14%). The influence of linker length and structure was evaluated, revealing that PEG6 chains and triazole-containing linkers provided higher conjugation efficiency. The results demonstrate the advantage of CuAAC-based bioconjugation for generating TE1PA-trastuzumab conjugates and support the use of these new chelators for copper-64/copper-67 theranostic applications.