MANOTA: a promising bifunctional chelating agent for copper-64 immunoPET.
Fiche publication
Date publication
septembre 2017
Journal
Dalton transactions (Cambridge, England : 2003)
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BRUNOTTE François, Pr DENAT Franck, Dr COLLIN Bertrand
Tous les auteurs :
Moreau M, Poty S, Vrigneaud JM, Walker P, Guillemin M, Raguin O, Oudot A, Bernhard C, Goze C, Boschetti F, Collin B, Brunotte F, Denat F
Lien Pubmed
Résumé
Improved bifunctional chelating agents (BFC) are required for copper-64 radiolabelling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific imaging agents. Four different bifunctional chelating agents (BFC) were evaluated for Fab (Fragment antigen binding) conjugation and radiolabelling with copper-64. Two DOTA- (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and two NOTA- (1,4,7-triazacyclononane-1,4,7-triacetic acid) derivatives bearing a p-benzyl-isothiocyanate group were conjugated to Fab-trastuzumab - which targets the HER2/neu receptor - and the average number of chelators attached ranged from 2.4 to 4.3 macrocycles per Fab. Labelling of the immunoconjugate with copper-64 was achieved in high radiochemical yields after 45 min at 37 °C, and the radiochemical purity of each (64)Cu-BFC-Fab-trastuzumab reached 97% after purification. The affinity of each (64)Cu-BFC-Fab-trastuzumab ranged between 10 and 50 nM as evaluated by in vitro saturation assays using the HCC1954 breast cancer cell line. PET-MR imaging and biodistribution studies were performed in mice bearing breast cancer BT-474 xenografts. BT-474 tumours were clearly visualized on PET images at 4 and 24 hours post-injection. The tumour uptake of (64)Cu-BFC-Fab-trastuzumab reached 8.9 to 12.8% ID g(-1) 24 hours post-injection and significant differences in non-specific liver uptake were observed depending on the BFC conjugated, the lowest being observed with MANOTA. These results show that MANOTA is a valuable tool for copper-64 radiolabelling.
Mots clés
Animals, Cell Line, Tumor, Chelating Agents, chemistry, Copper Radioisotopes, Heterocyclic Compounds, 1-Ring, chemistry, Humans, Immunoconjugates, chemistry, Immunoglobulin Fab Fragments, chemistry, Mammary Neoplasms, Experimental, diagnostic imaging, Mice, Positron-Emission Tomography, methods, Tissue Distribution, Trastuzumab, chemistry
Référence
Dalton Trans. 2017 Sep;: