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Cyclam te1pa for ⁶⁴Cu PET imaging. Bioconjugation to antibody, radiolabeling and preclinical application in xenografted colorectal cancer

Frindel, Mathieu, Le Saëc, Patricia, Beyler, Maryline, Navarro, Anne-Sophie, Saï-Maurel, Catherine, Alliot, Cyrille, Chérel, Michel, Gestin, Jean-François, Faivre-Chauvet, Alain, Tripier, Raphaël
RSC advances 2017 v.7 no.15 pp. 9272-9283
EDTA (chelating agent), antibodies, antigens, chelating agents, chelation, chemical bonding, colorectal neoplasms, image analysis, in vivo studies, ligands, liver, mice, phenotype, positron-emission tomography, radioactivity, radiolabeling, superoxide dismutase
te1pa is a monopicolinate cyclam previously presented as a better ⁶⁴Cu chelator than dota, nota and other chelators with an improved biodistribution and in vivo resistance to transchelation. This study aimed to determine whether te1pa could improve the in vivo stability of ⁶⁴Cu chelation concerning radioimmunoconjugates in order to obtain better contrast in PET imaging. te1pa was activated on its remaining acid function to obtain a N-hydroxysulfosuccinimide ester and was then conjugated to the F6 mouse IgG1a (F6 mAb), directed against CEA (carcinoembryonic antigen), leading to the F6-te1pa immunoconjugate. F6-te1pa was compared to F6–C-dota, i.e. F6 mAb conjugated with a C-functionalized dota which is the only chelator used nowadays in preclinical trials for ⁶⁴Cu PET imaging. Immunoconjugates were radiolabeled with ⁶⁴Cu showing an equivalent conjugation rate of 1 ligand per mAb. The study of the complexation kinetics highlighted a relatively fast process and ⁶⁴Cu–F6-te1pa, exhibiting a specific activity of 69.3 ± 28.9 MBq mg⁻¹, was proved to be inert since only 4.3% of radioactivity was transchelated from the ligand to EDTA (50 000 equiv., overnight) used as a competitor. All these results are comparable with C-functionalized dota. However, in vivo studies carried out in LS174T tumor-bearing nude mice showed a limited transchelation of superoxide dismutase (SOD) into the liver; 1.6% for ⁶⁴Cu–F6-te1pa after 24 h post-injection, compared to 4.3% for ⁶⁴Cu–F6–C-dota. The uptake of ⁶⁴Cu–F6-te1pa in tumors and radioactivity distribution in organs after 24 and 48 h was satisfactory and equivalent to various standards presented in the literature. Finally, PET-phenotypic images obtained with ⁶⁴Cu–F6-te1pa at 24 h post-injection showed an excellent contrast between tumors and the healthy tissues around, which agrees well with the results of the biodistribution. The usefulness of te1pa for PET phenotypic imaging using ⁶⁴Cu has been validated. The synthesis of a bifunctional derivative of te1pa will be the next step of this work to keep the ligand properties intact.