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Modular CuAAC-Based Synthesis of C-Functional Cyclam-Picolinate Chelators for Antibody Conjugation
Cédric Ollier1, Dyhia Amrane1,2, Guillaume Gabant3
1Univ Brest, UMR CNRS 6521 CEMCA, 6 Avenue Victor le Gorgeu, 29238 Brest, France.
The Journal of Organic Chemistry
|April 1, 2026
Summary
A new modular strategy enables efficient site-selective bioconjugation of TE1PA copper chelators using click chemistry. This method significantly improves chelator-to-antibody ratios for targeted cancer theranostics.
Area of Science:
- Medicinal Chemistry
- Bioconjugation Chemistry
- Radiopharmaceutical Chemistry
Background:
- TE1PA is a cyclam-based copper chelator crucial for nuclear medicine applications.
- Efficient and site-selective bioconjugation of chelators to antibodies is essential for developing targeted radiopharmaceuticals.
Purpose of the Study:
- To develop a modular strategy for bifunctionalizing TE1PA using Cu(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC) and thiol-maleimide chemistry.
- To enable site-selective bioconjugation of TE1PA to antibodies for theranostic applications.
Main Methods:
- Synthesis of an alkyne-functionalized TE1PA derivative.
- Coupling of TE1PA derivatives to azido-functionalized linkers (PEG3-biotin, PEG-maleimide) via CuAAC.
- Conjugation of maleimide-TE1PA derivatives to trastuzumab via cysteine residues.
Main Results:
- Triazole-linked TE1PA conjugates were synthesized in high yields (50-82%).
- TE1PA-trastuzumab immunoconjugates achieved high chelator-to-antibody ratios (CARs) of 2.2-3.8 with satisfactory yields (59-78%).
- CuAAC-based bioconjugation demonstrated superior efficiency compared to conventional peptide coupling methods.
Conclusions:
- The developed modular strategy offers an efficient approach for site-selective bioconjugation of TE1PA.
- These TE1PA-trastuzumab conjugates are promising for copper-64/copper-67 theranostic applications in nuclear medicine.
