Structure and stability of hexadentate complexes of ligands based on AAZTA for efficient PET labelling with gallium-68

Abstract

Pre-organised tricarboxylate ligands based on 6-amino-perhydro-1,4-diazepine bind (68)Ga rapidly and selectively in acetate buffer at pH 4 to 7, forming kinetically stable complexes suitable for use in PET imaging.

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

“…Further protonations occur at one of the ring-carboxylate groups and non-protonated ring nitrogen atom and/or the carboxylate pendant arms, respectively. According to the Δδ H values of the non-labile protons of the DATA m ligand published by Waldron et al [24] the protonation scheme of DATA m and DATA 5m ligands is very similar to that of AAZTA. A comparison of the protonation constants ( [28] it is reasonable to assume that the third protonation of DATA 5m involves the carboxylate group of the nvaleric acid pendant.…”

“…[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.…”

“…The solution structure of Ga(DATA 5m ) -is expected to be similar to that of the corresponding Ga(DATA m ), investigated in the solid state by Xray diffraction. [24] Crystallographic data of Ga(DATA m ) reveal, that the coordination geometry around each Ga 3+ -ion can be described as a slightly distorted octahedral geometry, where one of the ring N, the exocyclic N, one of the ring carboxylate O and the exocyclic carboxylate O donor atoms are coordinated in a square planar fashion in equatorial positions. The other ring N and ring carboxylate O donor atoms complete the coordination sphere of the Ga 3+ -ion in axial positions.…”

“…The other ring N and ring carboxylate O donor atoms complete the coordination sphere of the Ga 3+ -ion in axial positions. [24] In the 1 H-NMR spectra (273 K and pH=6.4), signals of the CH 3 -N and CH 3 -C in Ga(DATA m ) and the CH 3 -N in Ga(DATA 5m ) give rise to two singlets. By increasing the temperature, the singlets broaden, coalesce (Ga(DATA m ): CH 3 -C, T=283 K; CH 3 -N, T=298 K; Ga(DATA 5m ): CH 3 -N, T=298 K) and then merge into a single resonance (Figures 5 and S4).…”

“…[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. [24,25] Scheme 1. Structure of AAZTA, DATA m and DATA 5m ligands Radiolabeling experiments with 68 Ga of these ligands showed high radiochemical yields after 1 minute and high stability in the first in vitro and in vivo studies.…”