Gallium(III) chelates of mixed phosphonate-carboxylate triazamacrocyclic ligands relevant to nuclear medicine: Structural, stability and in vivo studies

Three triaza macrocyclic ligands, H₆NOTP (1,4,7-triazacyclononane-N,N′,N″-trimethylene phosphonic acid), H₄NO2AP (1,4,7-triazacyclononane-N-methylenephosphonic acid-N′,N″-dimethylenecarboxylic acid), and H₅NOA2P (1,4,7-triazacyclononane-N,N′-bis(methylenephosphonic acid)-N″-methylene carboxylic acid), and their gallium(III) chelates were studied in view of their potential interest as scintigraphic and PET (Positron Emission Tomography) imaging agents. A ¹H, ³¹P and ⁷¹Ga multinuclear NMR study gave an insight on the structure, internal dynamics and stability of the chelates in aqueous solution. In particular, the analysis of ⁷¹Ga NMR spectra gave information on the symmetry of the Ga^{3 +} coordination sphere and the stability of the chelates towards hydrolysis. The ³¹P NMR spectra afforded information on the protonation of the non-coordinated oxygen atoms from the pendant phosphonate groups and on the number of species in solution. The ¹H NMR spectra allowed the analysis of the structure and the number of species in solution. ³¹P and ¹H NMR titrations combined with potentiometry afforded the measurement of the protonation constants (log K_Hi) and the microscopic protonation scheme of the triaza macrocyclic ligands. The remarkably high thermodynamic stability constant (log K_GaL = 34.44 (0.04) and stepwise protonation constants of Ga(NOA2P)^{2 −} were determined by potentiometry and ⁶⁹Ga and ³¹P NMR titrations. Biodistribution and gamma imaging studies have been performed on Wistar rats using the radiolabeled ⁶⁷Ga(NO2AP)⁻ and ⁶⁷Ga(NOA2P)^{2 −} chelates, having both demonstrated to have renal excretion. The correlation of the molecular properties of the chelates with their pharmacokinetic properties has been analysed.