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

Three triaza macrocyclic ligands, HNOTP (1,4,7-triazacyclononane-N,N',N″-trimethylene phosphonic acid), HNO2AP (1,4,7-triazacyclononane-N-methylenephosphonic acid-N',N″-dimethylenecarboxylic acid), and HNOA2P (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 H, P and Ga multinuclear NMR study gave an insight on the structure, internal dynamics and stability of the chelates in aqueous solution. In particular, the analysis of Ga NMR spectra gave information on the symmetry of the Ga coordination sphere and the stability of the chelates towards hydrolysis. The P 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 H NMR spectra allowed the analysis of the structure and the number of species in solution. P and H NMR titrations combined with potentiometry afforded the measurement of the protonation constants (log K) and the microscopic protonation scheme of the triaza macrocyclic ligands. The remarkably high thermodynamic stability constant (log K=34.44 (0.04) and stepwise protonation constants of Ga(NOA2P) were determined by potentiometry and Ga and P NMR titrations. Biodistribution and gamma imaging studies have been performed on Wistar rats using the radiolabeled Ga(NO2AP) and Ga(NOA2P)chelates, having both demonstrated to have renal excretion. The correlation of the molecular properties of the chelates with their pharmacokinetic properties has been analysed.