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

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, H noapy and H 2 noapa , as new Ga 3+ chelators for potential use in nuclear medicine. The corresponding Ga 3+ complexes were synthesized and structurally characterized in solution by 1 H and 13 C 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 noapa 2- were determined by potentiometric titrations, providing an overall basicity ∑log K i H ( i = 1-4) that increases in the order noapy - < noapa 2- < nota 3- with increases in the negative charge of the ligand. Stability constants determined by pH-potentiometric titrations supplemented with 71 Ga 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 )] - . 67 Ga radiolabeling studies were performed in order to demonstrate the potential of these chelators for 67/68 Ga-based radiopharmaceuticals. The labelings of H noapy and H 2 noapa were nearly identical, outperforming H 3 nota . Stability studies were conducted in phosphate-buffered saline and in the presence of human serum transferrin, revealing no significant decomplexation of [ 67 Ga][Ga( noapy )] 2+ and [ 67 Ga][Ga( noapa )] + compared to [ 67 Ga][Ga( nota )]. Finally, all complexes were found to be highly hydrophilic, with calculated log D 7.4 values of -3.42 ± 0.05, -3.34 ± 0.04, and -3.00 ± 0.23 for H noapy , H 2 noapa , and H 3 nota , respectively, correlating with the charge of each complex and the electrostatic potentials obtained with DFT.