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

• Published in: RSC advances Vol. 7; no. 15; pp. 9272 - 9283
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Royal Society of Chemistry 2017
• Subjects: Cancer; Life Sciences
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/C6RA26003A

te1pa is a monopicolinate cyclam previously presented as a better
64
Cu 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
64
Cu 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
64
Cu PET imaging. Immunoconjugates were radiolabeled with
64
Cu showing an equivalent conjugation rate of 1 ligand per mAb. The study of the complexation kinetics highlighted a relatively fast process and
64
Cu–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
64
Cu–F6-te1pa after 24 h post-injection, compared to 4.3% for
64
Cu–F6–C-dota. The uptake of
64
Cu–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
64
Cu–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
64
Cu 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.