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 H2 noapa, 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 H2 noapa were nearly identical, outperforming H3 nota. 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, H2 noapa, and H3 nota, respectively, correlating with the charge of each complex and the electrostatic potentials obtained with DFT.

Pentadentate and Hexadentate Pyridinophane Ligands Support Reversible Cu(II)/Cu(I) Redox Couples

“…Analysis using HypSpec provided four pKa values, the highest of which, 11.13, is assigned to the deprotonation of the methyl amine nitrogen (Table 4). The next highest value, 9.16, is assigned to the deprotonation of the tertiary amine amended with the 2-methylpyridine arm, which has previously been shown to lower the basicity of amine nitrogens attached to it [34][35][36]. This assignment also aligns with the highest pKa observed in Pic N4, which contains two similar amine sites.…”

Novel [68Ga/177Lu]Ga/Lu-AZ-093 as PSMA-Targeting Agent for Diagnosis and Radiotherapy

“…The FDA has approved Netspot, gallium-68 dotatate, and Lutathera, lutetium-177 dotatate, for imaging and radioligand therapy (RLT) of neuroendocrine tumor. Advantages and disadvantages of macrocyclic DOTA, NOTA, and their related chelating groups, DOTAGA, α-(2-carboxyethyl)-1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraaceticacid, NOTAGA, 1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid, , etc., have been reviewed. − In addition, series of acyclic chelators, DTPA, HBED, AAZTA, etc., , have been reported. Many DOTA and DTPA derivatives have been successfully developed in recent years as new chelating agents by which forming stable metal complexes with enhanced properties for radiopharmaceuticals. ,,− Originally, AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid), a heptadentate chelator, was first reported by Aime et al designed to form gadolinium (Gd) complexes as MRI contrast imaging agents.…”