H3nota Derivatives Possessing Picolyl and Picolinate Pendants for Ga3+ Coordination and 67Ga3+ 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 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 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 D_7.4 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.