H-3 nota Derivatives Possessing Picolyl and Picolinate Pendants for Ga3+ Coordination and Ga-67(3+) Radiolabeling

We synthesized, thanks to the regiospecific N-functionalizationusing an orthoamide intermediate, two 1,4,7-triazacyclononane derivativescontaining an acetate arm and either a methylpyridine or a picolinicacid group, respectively, Hnoapy and H-2 noapa, as new Ga3+ chelators for potential usein nuclear medicine. The corresponding Ga3+ complexes weresynthesized and structurally characterized in solution by H-1 and C-13 NMR. The [Ga(noapy)](2+) complex appears to exist in solution as two diasteroisomeric pairsof enantiomers, as confirmed by density functional theory (DFT) calculations,while for [Ga(noapa)](+), a single species ispresent in solution. Solid-state investigations were possible forthe [Ga(noapa)](+) complex, which crystallizedfrom water as a pair of enantiomers. The average length of the N-Gabonds of 2.090 & ANGS; is identical with that found for the [Ga(nota)] complex, showing that the presence of the picolinatearm does not hinder the coordination of the ligand to the metal ion.Protonation constants of noapy ( - ) and noapa ( 2- ) weredetermined by potentiometric titrations, providing an overall basicity n-ary sumation log K ( i ) (H) (i = 1-4) that increases in the order noapy ( - ) < noapa ( 2- ) < nota ( 3- ) with increases in the negative charge of theligand. Stability constants determined by pH-potentiometric titrationssupplemented with Ga-71 NMR data show that the stabilitiesof [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)](-). Ga-67 radiolabeling studies wereperformed in order to demonstrate the potential of these chelatorsfor Ga-67/68-based radiopharmaceuticals. The labelings ofHnoapy and H-2 noapa were nearlyidentical, outperforming H-3 nota. Stabilitystudies were conducted in phosphate-buffered saline and in the presenceof human serum transferrin, revealing no significant decomplexationof [Ga-67][Ga(noapy)](2+) and [Ga-67][Ga(noapa)](+) compared to [Ga-67][Ga(nota)]. Finally, all complexes were foundto be highly hydrophilic, with calculated log D (7.4) values of -3.42 & PLUSMN; 0.05, -3.34 & PLUSMN;0.04, and -3.00 & PLUSMN; 0.23 for Hnoapy, H-2 noapa, and H-3 nota, respectively,correlating with the charge of each complex and the electrostaticpotentials obtained with DFT. Hnoapy and H-2 noapa havebeen synthesized and studied as H-3 nota alternativesfor the complexation of Ga3+ and Ga-67/68, providingenhanced stability of the radiocomplex while maintaining good coordinationproperties.