TY - JOUR
T1 - AAZTA-Like Ligands Bearing Phenolate Arms as Efficient Chelators for 68Ga Labelling in vitro and in vivo
AU - Martinelli, Jonathan
AU - Zapelli, Leonardo Maria
AU - Boccalon, Mariangela
AU - Vágner, Adrienn
AU - Nagy, Gábor
AU - Fekete, Anikó
AU - Szikra, Dezső
AU - Trencsényi, György
AU - Baranyai, Zsolt
AU - Tei, Lorenzo
N1 - Publisher Copyright:
© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.
PY - 2023/4/13
Y1 - 2023/4/13
N2 - 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 logKGaL 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 (t1/2) at pH 7.4 of 76 h. Although also the hexadentate AAZ2A-exoHB chelator forms a stable (logKGaL=24.69) and inert (t1/2=33 h at pH 7.4) Ga(III) complex, the 68Ga 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 68Ga isotope, and the resulting radiotracer tested for its stability in human serum and then in vivo for targeting B16-F10 tumours with miniPET imaging.
AB - 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 logKGaL 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 (t1/2) at pH 7.4 of 76 h. Although also the hexadentate AAZ2A-exoHB chelator forms a stable (logKGaL=24.69) and inert (t1/2=33 h at pH 7.4) Ga(III) complex, the 68Ga 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 68Ga isotope, and the resulting radiotracer tested for its stability in human serum and then in vivo for targeting B16-F10 tumours with miniPET imaging.
KW - PET
KW - gallium
KW - imaging agents
KW - ligand design
KW - radiopharmaceuticals
KW - αβ integrin targeting
UR - http://www.scopus.com/inward/record.url?scp=85149771051&partnerID=8YFLogxK
U2 - 10.1002/chem.202203798
DO - 10.1002/chem.202203798
M3 - Article
SN - 0947-6539
VL - 29
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 21
M1 - e202203798
ER -