Abstract
In order to rationalize the influence of FeIII contamination on labeling with the 68Ga eluted from 68Ge/68Ga-generator, 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]) (H6TRAP). 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 31P-NMR spectroscopy in the pH range 4.5–6.5 in the presence of 5–40 fold HxTRAP(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 HxHBED(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− (logKFeL = 26.7) is very similar to that of [Ga(TRAP)]3− (logKGaL = 26.2). The rates of ligand exchange reaction of [Fe(TRAP)]3− and [Ga(TRAP)]3− with HxHBED(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 (t1/2) 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 [*logKGa(HL) = 10.4 and *logKFe(HL) = 9.9], which are much more stable than the [*Ga(HNOTA)]+ intermediate [*logKGa(HL) = 4.2]. Deprotonation and transformation of the monoprotonated [*M(HTRAP)]2− intermediates into the final complex occur via OH−-assisted reactions. Rate constants (kOH) characterizing the OH−-driven deprotonation and transformation of [* Ga(HTRAP)]2− and [*Fe(HTRAP)]2− intermediates are 1.4 × 105 M−1s−1 and 3.4 × 104 M−1s−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 68GaIII in presence of excess FeIII.
Highlights
Due to the wealth of obtainable information resulting in a high diagnostic value, medical imaging plays an ever-increasing role in modern personalized healthcare
The majority of nuclear imaging procedures still are scintigraphic or single photon emission computed tomography (SPECT) scans relying on the gamma-emitter 99mTc, recent times have seen a strong surge in positron emission tomograpy (PET), following introduction of scanners capable of simultaneous functional and morphological imaging utilizing PET and computed tomography (CT) in 2001 (Beyer et al, 2000)
Protonation equilibria of the TRAP6−, NOTA3− and Bha− ligands were studied by pH-potentiometry
Summary
Due to the wealth of obtainable information resulting in a high diagnostic value, medical imaging plays an ever-increasing role in modern personalized healthcare In this context, radionuclide based imaging modalities which exploit George Hevesy’s tracer principle (Levi, 1976) allow for unique functional diagnostics, because they enable monitoring of biological processes without significant interference with the investigated subject owing to minuscule amounts of administered active compound. These small benchtop devices, which act as cyclotron-independent continuous onsite nuclide sources, contain 68Ge adsorbed on an inorganic matrix, such as SnO2 or TiO2, while decay of 68Ge produces 68GaIII which can be eluted with dilute HCl (Notni, 2012; Rösch, 2013). Such eluate frequently contains small amounts of impurities originating from the sorbent (Simecek et al, 2013), such as TiIV and FeIII, CuII, ZnII, or AlIII in form of their aqua or chlorido complexes
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