Published on June 8, 2021 – Updated on July 20, 2021

This project aims to assess the radiochemical and pharmacological interest of a macrocyclic chelator of copper-64 for immuno-PET imaging applications.

SPECT/CT images of the biodistribution of 125I-trastuzumab in Balb/c mice orthotopically xenografted with HER2 positive human breast cancer cells (BT-474). Left: 24 h post-injection / right: 48 h post-injection. The arrow indicates the tumour location.

SPECT/CT images of the biodistribution of 125I-trastuzumab in Balb/c mice orthotopically xenografted with HER2 positive human breast cancer cells (BT-474). Left: 24 h post-injection / right: 48 h post-injection. The arrow indicates the tumour location.

Immuno-PET imaging requires the use of monoclonal antibodies (mAbs) or their fragments radiolabelled with positron-emitting radionuclides. Among them, copper-64 is of particular interest due to its low maximum positron energy and suitable half-life (t1/2 = 12.7 h, Eb+max  = 655 keV). However, the development of 64Cu-based immuno-PET radiotracers requires the use of copper-specific chelators, modified with functional groups allowing the bioconjugation, and commonly called bifunctional chelators (BFCs). The stability and kinetic inertness of copper-chelator complexes is of utmost importance and highly challenging to limit in vivo Cu(II)/Cu(I) bioreduction, transmetallation and/or transchelation with human copper-binding proteins.

Recently, the UMR 1240 IMoST INSERM/UCA developed a series of polyazamacrocyclic chelators conjugated to a quaternary ammonium group for 64Cu-based PET imaging of cartilage functionality and associated diseases (osteoarthritis, arthritis, chondrosarcoma, see WO2016016272). Among all [64Cu]Cu-complex investigated, one of them, obtained with mild radiolabelling conditions and fast reaction time, has demonstrated excellent in vivo kinetic inertness in studied animal models. All together, these results prompted us to explore the potential of this chelator for the 64Cu-radiolabelling of biomolecules especially for immuno-PET imaging applications.

To this end, a series of three BFCs (our chelator and commonly used NODAGA and DOTA azamacrocycles) will be synthesised. For an optimal comparison, the covalent linking of BFCs to the biomolecule (i.e. anti-HER2 mAb) will be achieved by strain-promoted azide-alkyne cycloaddition. After radiolabelling, the stability, immunoreactivity and pharmacokinetics of the corresponding radioimmunoconjugates will be studied in HER2 positive breast cancer models. This project is developed in collaboration with the GICC EA7501 laboratory of the University of Tours (Team IMT, Dr. Nicolas Joubert) and the GIP Arronax of Nantes.