H Derivatives Possessing Picolyl and Picolinate Pendants for Ga Coordination and Ga Radiolabeling.

We synthesized, thanks to the regiospecific -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, H and H, as new Ga chelators for potential use in nuclear medicine. The corresponding Ga complexes were synthesized and structurally characterized in solution by H and C NMR. The [Ga()] complex appears to exist in solution as two diasteroisomeric pairs of enantiomers, as confirmed by density functional theory (DFT) calculations, while for [Ga()], a single species is present in solution. Solid-state investigations were possible for the [Ga()] 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()] complex, showing that the presence of the picolinate arm does not hinder the coordination of the ligand to the metal ion. Protonation constants of and were determined by potentiometric titrations, providing an overall basicity ∑log ( = 1-4) that increases in the order < < with increases in the negative charge of the ligand. Stability constants determined by pH-potentiometric titrations supplemented with Ga NMR data show that the stabilities of [Ga()] and [Ga()] are lower compared to that of [Ga()] but higher than those of other standards such as [Ga()]. Ga radiolabeling studies were performed in order to demonstrate the potential of these chelators for Ga-based radiopharmaceuticals. The labelings of H and H were nearly identical, outperforming H. Stability studies were conducted in phosphate-buffered saline and in the presence of human serum transferrin, revealing no significant decomplexation of [Ga][Ga()] and [Ga][Ga()] compared to [Ga][Ga()]. Finally, all complexes were found to be highly hydrophilic, with calculated log values of -3.42 ± 0.05, -3.34 ± 0.04, and -3.00 ± 0.23 for H, H, and H, respectively, correlating with the charge of each complex and the electrostatic potentials obtained with DFT.