title: Improving the stability and inertness of Cu(ii) and Cu(i) complexes with methylthiazolyl ligands by tuning the macrocyclic structure.
abstract: A tacn based ligand bearing two methylthiazolyl arms (no2th) was synthesized with the aim to find ligands forming very stable and inert complexes with Cu(ii) and Cu(i) in aqueous medium for radiopharmaceutical applications. The no2th ligand was efficiently prepared following the orthoamide intermediate synthesis. The complexes with Cu(2+) and Zn(2+) were obtained and analyzed by X-ray diffraction. The [Cu(no2th)](2+) complex presents a pentacoordinated distorted square pyramidal coordination geometry, while the metal ion in [Zn(no2th)](2+) adopts a hexacoordinated distorted trigonal prismatic geometry involving the coordination of a perchlorate counter ion. The acid-base properties of no2th have been studied using potentiometric titrations, and the stability constants of Cu(2+) and Zn(2+) complexes were determined by potentiometric and UV-vis titrations using H4edta as a competitor ligand. The stability constant determined for the Cu(2+) complex is rather high (log KCuL = 20.77 and pCu = 17.15), and moreover no2th exhibits a high selectivity for copper(ii) in relation to zinc(ii). The kinetics of the copper(ii) complexation process is very fast even in acidic medium. In addition, the [Cu(no2th)](2+) complex was found to be inert under rather harsh conditions (up to 2 M HCl and 60 °C), displaying a very high half-life time of about 15 days in 2 M HCl at 90 °C. The electrochemical reduction of the copper(ii) complex in water leads to the reversible formation of a stable copper(i) species. Spectroscopic studies performed by NMR, UV-vis and EPR, assisted by theoretical calculations, show that the [Cu(no2th)](2+) complex presents a structure in solution similar to that observed in the solid state. When compared to its cyclam di-N-methylthiazolyl counterpart, the results reported in this paper unambiguously show that replacing the cyclam unit by a tacn moiety improves the stability and inertness of its Cu(ii) and Cu(i) complexes.
authors.affiliation: Université de Bretagne Occidentale, UMR-CNRS 6521, SFR ScInBioS, Faculté des Sciences et Techniques, 6 avenue Victor le Gorgeu, C.S. 93837, 29238 Brest Cedex 3, France. Raphael.tripier@univ-brest.fr.
authors.forename: Mariane
authors.initials: M
authors.lastname: Le Fur
authors.forename: Maryline
authors.initials: M
authors.lastname: Beyler
authors.forename: Nicolas
authors.initials: N
authors.lastname: Le Poul
authors.forename: Luís M P
authors.initials: LM
authors.lastname: Lima
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Mest
authors.forename: Rita
authors.initials: R
authors.lastname: Delgado
authors.forename: Carlos
authors.initials: C
authors.lastname: Platas-Iglesias
authors.forename: Véronique
authors.initials: V
authors.lastname: Patinec
authors.forename: Raphaël
authors.initials: R
authors.lastname: Tripier