Equilibrium Thermodynamics, Formation, and Dissociation Kinetics of Trivalent Iron and Gallium Complexes of Triazacyclononane-Triphosphinate (TRAP) Chelators: Unraveling the Foundations of Highly Selective Ga-68 Labeling

In order to rationalize the influence of Fe contamination on labeling with the Ga eluted from Ge/ Ga- enerator, a detailed investigation was carried out on the equilibrium properties, formation and dissociation kinetics of Ga - and Fe -complexes of 1,4,7-triazacyclononane-1,4,7-tris(methylene[2-carboxyethylphosphinic acid]) (H TRAP). The stability and protonation constants of the [Fe(TRAP)] complex were determined by pH-potentiometry and spectrophotometry by following the competition reaction between the TRAP ligand and benzhydroxamic acid (0.15 M NaNO , 25°C). The formation rates of [Fe(TRAP)] and [Ga(TRAP)] complexes were determined by spectrophotometry and P-NMR spectroscopy in the pH range 4.5-6.5 in the presence of 5-40 fold H TRAP excess (x = 1 and 2, 0.15 M NaNO , 25°C). The kinetic inertness of [Fe(TRAP)] and [Ga(TRAP)] was examined by the trans-chelation reactions with 10 to 20-fold excess of H HBED ligand by spectrophotometry at 25°C in 0.15 M NaCl (x = 0,1 and 2). The stability constant of [Fe(TRAP)] (log = 26.7) is very similar to that of [Ga(TRAP)] (log = 26.2). The rates of ligand exchange reaction of [Fe(TRAP)] and [Ga(TRAP)] with H HBED are similar. The reactions take place quite slowly via spontaneous dissociation of [M(TRAP)] , [M(TRAP)OH] and [M(TRAP)(OH) ] species. Dissociation half-lives ( ) of [Fe(TRAP)] and [Ga(TRAP)] complexes are 1.1 × 10 and 1.4 × 10 h at pH = 7.4 and 25°C. The formation reactions of [Fe(TRAP)] and [Ga(TRAP)] are also slow due to the formation of the unusually stable monoprotonated [ M(HTRAP)] intermediates [ log = 10.4 and log = 9.9], which are much more stable than the [ Ga(HNOTA)] intermediate [ log = 4.2]. Deprotonation and transformation of the monoprotonated [ M(HTRAP)] intermediates into the final complex occur via OH -assisted reactions. Rate constants ( ) characterizing the OH -driven deprotonation and transformation of [ Ga(HTRAP)] and [ Fe(HTRAP)] intermediates are 1.4 × 10 M s and 3.4 × 10 M s , respectively. In conclusion, the equilibrium and kinetic properties of [Fe(TRAP)] and [Ga(TRAP)] complexes are remarkably similar due to the close physico-chemical properties of Fe and Ga -ions. However, a slightly faster formation of [Ga(TRAP)] over [Fe(TRAP)] provides a rationale for a previously observed, selective complexation of Ga in presence of excess Fe .