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Synthesis of a C-functionalized TE1PA and comparison with analogues. Example of bioconjugation on 9E7.4 mAb for multiple myeloma 64Cu-PET imaging

Abstract

According to the excellent copper(II) and 64-copper(II) complexation of TE1PA ligand, a monopicolinate cyclam, in both aqueous medium and in vivo, we looked for a way to make it bifunctional, while keeping intact its chelating properties. Overcoming the already known drawback of a grafting by its carboxyl group, essential to the overall ligand assets, TE1PA bifunctional derivative bearing an additional isothiocyanate coupling function on a carbon atom of the macrocyclic ring was synthesized. This led to a comparable architecture of other bifunctional copper(II) chelators commercially available such as p-SCN-Bn-DOTA already used in clinical trials for 64Cu-immuno-PET imaging. The C functionalization of TE1PA on one carbon atom in β-N position of the cyclam backbone was successfully managed by adapting our patented methodology to the huge challenge to allow the regiospecific mono-N-functionalization of the unsymmetrical ligand. The so obtained ligand p-SCN-Bn-TE1PA was coupled to the 9E7.4 murine antibody (mAb), an IgG2a anti CD-138 for multiple myeloma (MM) targeting. The conjugation efficiency was checked by looking at the 64Cu radiolabeling and the radiopharmaceutical 64Cu-9E7.4-p-SCN-Bn-TE1PA immunoreactivity and especially by comparison with 9E7.4 p SCN-Bn-NOTA and 9E7.4-p-SCN-Bn-DOTA obtained respectively from commercially and presumed highly efficient chelators NOTA and DOTA. Results are quite clear, showing with p-SCN-Bn-TE1PA a coupling rate 5 times higher and an immunoreactivity of 1.5 to 2 times greater than its two competitors. p-SCN-Bn-TE1PA also outperforms TE1PA conjugated via its carboxylic function on the same antibody. A first 64Cu-immuno-PET preclinical study in a syngeneic model of MM was achieved confirming the high in vivo properties of 64Cu-9E7.4-p-SCN-Bn-TE1PA for PET imaging, looking at the high clearance already after 24 h and a particularly important tumor-to-liver ratio increasing at 48 h.

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Publication details

The article was received on 27 Feb 2018, accepted on 05 Apr 2018 and first published on 10 Apr 2018


Article type: Paper
DOI: 10.1039/C8OB00499D
Citation: Org. Biomol. Chem., 2018, Accepted Manuscript
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    Synthesis of a C-functionalized TE1PA and comparison with analogues. Example of bioconjugation on 9E7.4 mAb for multiple myeloma 64Cu-PET imaging

    T. Le Bihan, A. Navarro, L. B. Nathalie, P. Le Saec, S. Gouard, F. Haddad, J. Gestin, M. Cherel, A. Faivre Chauvet and R. Tripier, Org. Biomol. Chem., 2018, Accepted Manuscript , DOI: 10.1039/C8OB00499D

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