Objectives: The importance of ⁶⁸Ga in PET has been markedly increased due to the availability of ⁶⁸Ga via ⁶⁸Ge/⁶⁸Ga generators. In PET/CT applications, the ⁶⁸Ga isotope must be complexed with an appropriate bifunctional ligand (BFC) conjugated to e.g. peptides. The ⁶⁸Ga-BFC complexes should have high stability and kinetic inertness under physiological conditions. These requirements are fulfilled by the use of the semi-macrocyclic AAZTA ligand.¹ Here we report the physico-chemical properties of two hexadentate AAZTA derivatives (DATA^m and DATA5^m) proposed for the complexation of ⁶⁸Ga. ²

Scheme 1. The formula of H₃DATA^m, H₄DATA5^m and H₄AAZTA ligands

Results: The stability constants of the Ga(DATA^m) and Ga(DATA5^m) complexes (logK_Ga(DATAm)=21.78, logK_Ga(DATA5m)=21.32) are similar to that of Ga(AAZTA) (logK_Ga(AAZTA)=21.15). The formation of Ga(DATA^m)OH and Ga(DATA5^m)OH complexes has been detected at pH>5.0. Transformation between GaL and Ga(L)OH species is a rather slow process, which might take place by structural rearrangement of the Ga(DATA^m) and Ga(DATA5^m) complexes. The transmetallation and ligand exchange reactions of Ga(DATA^m) and Ga(DATA5^m) complexes take place through a slow OH^- assisted dissociation of the Ga(III)-complexes, followed by the fast reactions between the exchanging Cu²⁺-ion and the free DATA ligands, while the free Ga³⁺-ion may react with transferrin, respectively. The dissociation reactions of Ga(DATA^m) and Ga(DATA5^m) are similar and somewhat faster compared to Ga(AAZTA) at physiological condition (Ga(DATA^m) and Ga(DATA5^m): t_½=11 h, Ga(AAZTA): t_½=23 h, pH=7.4, 25°C).¹

Conclusion: The high stability, the fast formation and the relatively slow dissociation reactions are promising for the diagnostic applications of radioactive Ga(DATA^m) and Ga(DATA5^m) complexes, they are suitable for in vivo experiments.

¹ Zs. Baranyai et al., Eur. J. Inorg. Chem., 2013, 147 – 162.

²  B. P. Waldron et al., Chem. Commun., 2013, 49, 579