AAZTA-Like Ligands Bearing Phenolate Arms as Efficient Chelators for 68 Ga Labelling in vitro and in vivo

• Published in: Chemistry : a European journal Vol. 29; no. 21; p. e202203798
• Main Authors: Martinelli, Jonathan, Zapelli, Leonardo Maria, Boccalon, Mariangela, Vágner, Adrienn, Nagy, Gábor, Fekete, Anikó, Szikra, Dezső, Trencsényi, György, Baranyai, Zsolt, Tei, Lorenzo
• Format: Journal Article
• Language: English
• Published: Germany 13-04-2023
• Subjects: Arm; Chelating Agents - chemistry; Gallium Radioisotopes - chemistry; Humans; Neoplasms; Positron-Emission Tomography - methods; Radiopharmaceuticals - chemistry; ligand design; radiopharmaceuticals; gallium; imaging agents; αvβ3 integrin targeting; PET
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202203798

The introduction of a phenolate pendant arm in place of an acetate on AAZTA- and DATA-like ligands resulted in hepta- and hexadentate chelators able to form Ga(III) complexes with thermodynamic stability and kinetic inertness higher than that of other Ga(III) complexes based on the parent 6-amino-6-methylperhydro-1,4-diazepine scaffold. In particular, the heptadentate AAZ3A-endoHB with a phenolate arm on an endocyclic N-atom shows a logK
of 27.35 and a remarkable resistance to hydroxide coordination up to basic pH (pH>9). This behaviour allows to also improve the kinetic inertness of the complex showing a dissociation half-life (t
) at pH 7.4 of 76 h. Although also the hexadentate AAZ2A-exoHB chelator forms a stable (logK
=24.69) and inert (t
=33 h at pH 7.4) Ga(III) complex, the
Ga labelling showed a better radiochemical yield with AAZ3A-endoHB, especially at room temperature. Thus, a bifunctional chelator of AAZ3A-endoHB was synthesized bearing an isothiocyanate group that was conjugated to the N-terminus of a c(RGD) peptide for integrin receptor targeting. Finally, the conjugate was successfully labelled with
Ga isotope, and the resulting radiotracer tested for its stability in human serum and then in vivo for targeting B16-F10 tumours with miniPET imaging.