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 FeIII contamination on labeling with the 68 Ga eluted from 68 Ge/68 Ga- g enerator, a detailed investigation was carried out on the equilibrium properties, formation and dissociation kinetics of GaIII - and FeIII -complexes of 1,4,7-triazacyclononane-1,4,7-tris(methylene[2-carboxyethylphosphinic acid]) (H6 TRAP). The stability and protonation constants of the [Fe(TRAP)]3- complex were determined by pH-potentiometry and spectrophotometry by following the competition reaction between the TRAP ligand and benzhydroxamic acid (0.15 M NaNO3 , 25°C). The formation rates of [Fe(TRAP)] and [Ga(TRAP)] complexes were determined by spectrophotometry and 31 P-NMR spectroscopy in the pH range 4.5-6.5 in the presence of 5-40 fold Hx TRAP(x-6) excess (x = 1 and 2, 0.15 M NaNO3 , 25°C). The kinetic inertness of [Fe(TRAP)]3- and [Ga(TRAP)]3- was examined by the trans-chelation reactions with 10 to 20-fold excess of Hx HBED(x-4) ligand by spectrophotometry at 25°C in 0.15 M NaCl (x = 0,1 and 2). The stability constant of [Fe(TRAP)]3- (log K FeL = 26.7) is very similar to that of [Ga(TRAP)]3- (log K GaL = 26.2). The rates of ligand exchange reaction of [Fe(TRAP)]3- and [Ga(TRAP)]3- with Hx HBED(x-4) are similar. The reactions take place quite slowly via spontaneous dissociation of [M(TRAP)]3- , [M(TRAP)OH]4- and [M(TRAP)(OH)2 ]5- species. Dissociation half-lives ( t 1/2 ) of [Fe(TRAP)]3- and [Ga(TRAP)]3- complexes are 1.1 × 105 and 1.4 × 105 h at pH = 7.4 and 25°C. The formation reactions of [Fe(TRAP)]3- and [Ga(TRAP)]3- are also slow due to the formation of the unusually stable monoprotonated [* M(HTRAP)]2- intermediates [* log K Ga(HL) = 10.4 and * log K Fe(HL) = 9.9], which are much more stable than the [* Ga(HNOTA)]+ intermediate [* log K Ga(HL) = 4.2]. Deprotonation and transformation of the monoprotonated [* M(HTRAP)]2- intermediates into the final complex occur via OH- -assisted reactions. Rate constants ( k OH ) characterizing the OH- -driven deprotonation and transformation of [* Ga(HTRAP)]2- and [* Fe(HTRAP)]2- intermediates are 1.4 × 105 M-1 s-1 and 3.4 × 104 M-1 s-1 , 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 FeIII and GaIII -ions. However, a slightly faster formation of [Ga(TRAP)] over [Fe(TRAP)] provides a rationale for a previously observed, selective complexation of 68 GaIII in presence of excess FeIII .