H 3 nota Derivatives Possessing Picolyl and Picolinate Pendants for Ga 3+ Coordination and 67 Ga 3+ Radiolabeling - Université de Bretagne Occidentale Access content directly
Journal Articles Inorganic Chemistry Year : 2023

H 3 nota Derivatives Possessing Picolyl and Picolinate Pendants for Ga 3+ Coordination and 67 Ga 3+ Radiolabeling

Abstract

We synthesized, thanks to the regiospecific N-functionalization using an orthoamide intermediate, two 1,4,7-triazacyclononane derivatives containing an acetate arm and either a methylpyridine or a picolinic acid group, respectively, Hnoapy and H2noapa, as new Ga3+ chelators for potential use in nuclear medicine. The corresponding Ga3+ complexes were synthesized and structurally characterized in solution by 1H and 13C NMR. The [Ga(noapy)]2+ complex appears to exist in solution as two diasteroisomeric pairs of enantiomers, as confirmed by density functional theory (DFT) calculations, while for [Ga(noapa)]+, a single species is present in solution. Solid-state investigations were possible for the [Ga(noapa)]+ complex, which crystallized from water as a pair of enantiomers. The average length of the N–Ga bonds of 2.090 Å is identical with that found for the [Ga(nota)] complex, showing that the presence of the picolinate arm does not hinder the coordination of the ligand to the metal ion. Protonation constants of noapy– and noapa2– were determined by potentiometric titrations, providing an overall basicity ∑log KiH (i = 1–4) that increases in the order noapy– < noapa2– < nota3– with increases in the negative charge of the ligand. Stability constants determined by pH-potentiometric titrations supplemented with 71Ga NMR data show that the stabilities of [Ga(noapy)]2+ and [Ga(noapa)]+ are lower compared to that of [Ga(nota)] but higher than those of other standards such as [Ga(aazta)]−. 67Ga radiolabeling studies were performed in order to demonstrate the potential of these chelators for 67/68Ga-based radiopharmaceuticals. The labelings of Hnoapy and H2noapa were nearly identical, outperforming H3nota. Stability studies were conducted in phosphate-buffered saline and in the presence of human serum transferrin, revealing no significant decomplexation of [67Ga][Ga(noapy)]2+ and [67Ga][Ga(noapa)]+ compared to [67Ga][Ga(nota)]. Finally, all complexes were found to be highly hydrophilic, with calculated log D7.4 values of −3.42 ± 0.05, −3.34 ± 0.04, and −3.00 ± 0.23 for Hnoapy, H2noapa, and H3nota, respectively, correlating with the charge of each complex and the electrostatic potentials obtained with DFT.
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Dates and versions

hal-04545822 , version 1 (14-04-2024)

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Axia Marlin, Angus Koller, Enikö Madarasi, Marie Cordier, David Esteban-Gómez, et al.. H 3 nota Derivatives Possessing Picolyl and Picolinate Pendants for Ga 3+ Coordination and 67 Ga 3+ Radiolabeling. Inorganic Chemistry, 2023, 62 (50), pp.20634-20645. ⟨10.1021/acs.inorgchem.3c01417⟩. ⟨hal-04545822⟩
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