Extraordinary Similarities of Formation and Dissociation Kinetics of Fe<sup>III</sup>- and Ga<sup>III</sup>- TRAP-Pr Complexes — ASN Events
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Extraordinary Similarities of Formation and Dissociation Kinetics of FeIII- and GaIII- TRAP-Pr Complexes (#123)

Imre Toth 1 , Adrienn Vágner 1 , Attila Forgács 2 , Ernő Brücher 1 , Hans-Jürgen Wester 3 , Johannes Notni 3 , Zsolt Baranyai 4
  1. University of Debrecen, Debrecen, HAJDU BIHAR, Hungary
  2. Dipartimento di Scienze ed Innovazione Tecnologica, Università del Piemonte Orientale "Amedeo Avogadro", Alessandria, Italy
  3. Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, München, Germany
  4. CRB/Discovery Trieste, Bracco Imaging S.p.A, Basovizza Trieste, Italy

Objectives: Among the β+-emitting radiometals 68Ga has the most promising properties for translational PET applications. 68Ga is often produced in 68Ge/68Ga radioisotope generators with inorganic matrix, such as SnO2 or TiO2. Hence, the eluate frequently contains ionic impurities, such as TiIV and FeIII in form of aqua or chloro complexes. The equilibrium and kinetic properties of FeIII-complexes formed with the chelators must be known in order to assess the influence of Fe3+ on the complexation of 68Ga3+ by amino-polycarboxylate ligands.1 1,4,7-triazacyclononane-1,4,7-triphosphinic acids (TRAP) are reported to be efficient 68Ga3+ chelators.2 Herein we summarize a detailed investigation on the equilibrium and kinetic behaviour of GaIII- and FeIII-complexes formed with a TRAP derivative, functionalized with the propionic acid pendant arm (TRAP-Pr).

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Scheme 1. Formula of TRAP-Pr and HBED ligands

Results: The stability constant of Fe(TRAP-Pr) (logKFeL=26.73) is very similar to that of Ga(TRAP-Pr) (logKGaL=26.24).2 The formation of the Fe(TRAP-Pr)OH and Ga(TRAP-Pr)OH complex has been detected at pH>8.0. Transchelation reactions of Ga(TRAP-Pr) and Fe(TRAP-Pr) with HBED take place very slowly via spontaneous (kOH) and hydroxide-assisted (kOH2) dissociation of GaL(OH) and FeL(OH) species characterized with similar kOH=4x10-3 M-1s-1 and kOH2=13.5 M-2s-1  rate constants. The formation of Fe(TRAP-Pr) complex is very slow due to the unusually stable monoprotonated *Fe(HTRAP-Pr) intermediate  (*logKFe(HL)=9.9). The rate determining step is the OH- assisted deprotonation of the *Fe(HTRAP-Pr) intermediate (kOH=3.4x10-4 M-1s-1) followed by its rearrangement to the final Fe(TRAP-Pr) complex.

Conclusion: The equilibrium and kinetic properties of Fe(TRAP-Pr) and Ga(TRAP-Pr) complexes are bewilderingly similar due to the close physico-chemical nature of Fe3+ and Ga3+-ions. It may results in serious difficulties during the labeling process.

1 I. Velikyan, Molecules, 2015, 20, 12913; I. Velikyan, Theranostics 2014, 4, 47–80.

2 J. Notni et al., Chem. Eur. J. 2010, 16, 7174–7185.