TE1PA as Innovating Chelator for 64 Cu Immuno-TEP Imaging: A Comparative in Vivo Study with DOTA/NOTA by Conjugation on 9E7.4 mAb in a Syngeneic Multiple Myeloma Model

Following the successful synthesis of a -functionalized version of the TE1PA ligand, a monopicolinate cyclam, we looked to demonstrate its in vivo properties versus DOTA and NOTA, after conjugation on the 9E7.4 rat antibody, an IgG against CD138 murine, which has relevant properties for multiple myeloma targeting. For each ligand, different conjugation approaches had been considered to select the most appropriate for the comparative study. The -SCN-Bn-TE1PA, NHS-DOTA, and -SCN-Bn-NOTA were finally chosen for conjugation and radiolabeling tests. For in vivo comparison, we used a model of subcutaneous grafted mice with 5T33 tumor cells. In vitro tests and immuno-PET study highlighted Cu-9E7.4- -SCN-Bn-NOTA as the least attractive. Further competitive biodistribution and hepatic metabolic studies at 2, 24, and 48 h post-injection (100 μg radiolabeled with 10 MBq of Cu) were then performed with the Cu-9E7.4- -SCN-Bn-TE1PA and Cu-9E7.4-NHS-DOTA. Results show a better in vivo resistance of Cu-9E7.4- -SCN-Bn-TE1PA to transchelation compared to Cu-9E7.4-NHS-DOTA, especially at later times. This was confirmed with Cu-9E7.4- -SCN-Bn-NOTA at 48 h PI. Cu-9E7.4- -SCN-Bn-TE1PA also demonstrated an excellent hepatic clearance. Cu-9E7.4- -SCN-Bn-TE1PA displayed an overall superiority compared to Cu-9E7.4-NHS-DOTA and Cu-9E7.4- -SCN-Bn-NOTA in terms of in vivo stability, reinforcing the usefulness of the SCN-Bn-TE1PA ligand for Cu immuno-PET imaging.