Equilibrium, Kinetic and Structural Studies of AAZTA Complexes with Ga³⁺, In³⁺ and Cu²⁺

Abstract

A detailed study of the structures, thermodynamic stabilities and kinetics of the dissociation of Ga3+, In3+ and Cu2+ complexes formed with the heptadentate ligand AAZTA is reported. The stability constants (log KML) of the AAZTA complexes of Ga3+, In3+ and Cu2+ are 22.18, 29.58 and 22.27, respectively, which suggests that the seven‐membered‐ring skeleton is suited to the accommodation of these metal ions. The solid‐state structure of [Cu(H2AAZTA)]·H2O shows a distorted octahedral coordination. The equatorial coordination sites of Cu2+ are occupied by one of the ring N atoms, a water O atom, one of the carboxylate O atoms and the N atom of the iminodiacetate moiety. The other ring N atom and the carboxylate O atom of the iminodiacetate moiety coordinate to the Cu2+ in the axial positions. In the pH range 4.5–8.5, Ga3+ is present in the form of the highly stable [Ga(AAZTA)OH]2– (log βGaLH–1 = 17.69) The exchange reactions of [Ga(AAZTA)OH]2– with Cu2+ and transferrin are very slow and mainly occur through the spontaneous dissociation of the complex close to physiological conditions. The half‐life for the dissociation of [Ga(AAZTA)OH]2– is t1/2 = 23 h at pH = 7.5 and 25 °C in 0.025 M NaHCO3 and 0.15 M NaCl. The high conditional stability, fast formation and sufficiently slow dissociation of [Ga(AAZTA)OH]2– represent promising properties for the complexation and diagnostic applications of radioactive Ga isotopes.

Equilibrium, Kinetic and Structural Properties of Gallium(III) and Some Divalent Metal Complexes Formed with the New DATAm and DATA5m Ligands

“…[27] (MeAAZ3A=DATA m ); [b] Ref. [17]; [c] The protonation constant of n-valeric acid is not considered (due to the negligible role in metal binding).…”

“…[a] Ref. [17] The stability constants of Ga(DATA m ) and Ga(DATA 5m ) complexes are slightly higher than those of Ga(AAZTA). Since the total basicity (ΣlogK i H ) of AAZTA is significantly higher than those of DATA m and DATA 5m (Table 1), the higher logK GaL values of Ga(DATA m ) and Ga(DATA 5m ) can be explained by considering the structural properties of these complexes.…”

“…[24,25] However, in Ga(AAZTA) the Ga 3+ ion is coordinated by 3 amine-N and 3 carboxylate-O donor atoms (two exocyclic-and one ring-carboxylate-O, whereas one of the ring-carboxylate-O does not coordinate) with a more distorted octahedral geometry, that results in a less favourable coordination environment for the Ga 3+ -ion and the lower stability of Ga(AAZTA). [17] By taking into account these assumptions and presuming similar coordination geometry for the Ga III -and Zn II -complexes, the higher stability of the Zn(DATA m ) and Zn(DATA 5m ) by comparing with that of Zn(AAZTA) might also be explained by the less favourable coordination environment of the Zn II ion in the more distorted Zn(AAZTA) complex. Owing to the higher stability of the Ga(DATA m ) and Ga (DATA 5m In the species distribution diagrams (Figures 4 and S3 (Figures 2 and S1).…”

“…However, the 71 Ga-NMR signal of the Ga(AAZTA) -is even broader (δ Ga =118 ppm, ν ½ = 2218 Hz, pH=4.0) as a result of the more asymmetric coordination geometry of AAZTA. [17] In the pH range 3 -5, the protonation of the n-valeric acid side chain of Ga(DATA 5m ) -takes place with a shift to higher frequency of the -CH 2 -COO -signal (triplet at 2.3 ppm, Figure S1). The protonation constant of n-valeric acid entity of Ga(DATA 5m ) -(logK GaHL =4.40, Table 3) is very similar to that of the free DATA 5m (logK 3 H =4.35, Table 1), which indicates, that the carboxylate group of n-valeric acid arm in DATA 5m does not coordinate to the Ga 3+ -ion, so it can protonate/deprotonate independently.…”

“…[15] Its coordination properties towards a wide array of metal ions have been reported, showing its remarkable affinities to lanthanides and transition metal ions. [16][17][18][19] The ready availability of AAZTA and recent descriptions of its lipophilic derivatives for targeting high density lipoproteins (HDL), [20] cell FULL PAPER membranes, [21] the synthesis of bifunctional compounds for conjugation purposes, [22] and the fast formation of complexes prompted us to explore the possibility of employing the AAZTA platform for developing useful complexes for targeted PET applications. [23] Based on the 6-amino-1,4-diazapine (DATA) scaffold new hexadentate chelators were developed by Waldron et al that shows favourable complexation behaviour.…”