title: Chemical, radiochemical and biological studies of new gallium(III) complexes with hexadentate chelators.
abstract: New N4O2-donor acyclic chelators 2-[[2-[2-(3,5-dimethylpyrazol-1-yl)ethyl-[2-[(2-hydroxyphenyl)methylamino]ethyl]amino]ethylamino]methyl]phenol (H2L(pz*,NH)) and 2-[[2-[2-[(2-hydroxyphenyl)methylamino]ethyl-(2-pyridylmethyl)amino]ethylamino]methyl]phenol (H2L(py,NH)) were obtained upon introduction of pyridyl or pyrazolyl coordinating units at the central nitrogen atom of diethylenetriamine (dien) and by functionalization of its terminal amines with phenol groups. The coordination behavior of H2L(pz*,NH) and H2L(py,NH) was evaluated towards (nat)Ga/(67)Ga, aiming to assess their suitability to obtain Ga(iii) chelates relevant for biomedical applications. Single crystal X-ray diffraction analysis of the complexes [GaL(pz*,NH)](ClO4) and [GaL(py,NH)](ClO4) confirmed the presence of N4O2-hexadentate chelators with the phenoxide groups coordinated cis relatively to the pyridyl/pyrazolyl arms. Unlike [GaL(pz*,NH)](ClO4), [GaL(py,NH)](ClO4) exists in solution as a mixture of isomers, as confirmed by several NMR techniques. The corresponding radiocomplex [(67)GaL(py,NH)](+) was obtained smoothly in almost quantitative radiochemical yield, contrary to [(67)GaL(pz*,NH)](+) that seems to be (hemi)labile under the same conditions. [(67)GaL(py,NH)](+) presents a high in vivo stability and a favourable biodistribution profile in mice. The imine congeners 2-[(E)-2-[2-(3,5-dimethylpyrazol-1-yl)ethyl-[2-[(E)-(2-hydroxyphenyl)methyleneamino]ethyl]amino]ethyliminomethyl]phenol (H2L(pz*,C[double bond, length as m-dash]N)) and 2-[(E)-2-[2-[(E)-(2-hydroxyphenyl)methyleneamino]ethyl-(2-pyridylmethyl)amino]ethyliminomethyl]phenol (H2L(py,C[double bond, length as m-dash]N)) were also evaluated but they did not form complexes compatible for biomedical applications owing to their high reactivity.
authors.affiliation: Centro de Ciências e Tecnologias e Nucleares, IST, Universidade de Lisboa, Estrada Nacional 10, 2695-066 Bobadela LRS, Portugal. apaulo@ctn.ist.utl.pt.
authors.forename: Francisco
authors.initials: F
authors.lastname: Silva
authors.forename: Maria Paula C
authors.initials: MP
authors.lastname: Campello
authors.forename: Lurdes
authors.initials: L
authors.lastname: Gano
authors.forename: Célia
authors.initials: C
authors.lastname: Fernandes
authors.forename: Isabel C
authors.initials: IC
authors.lastname: Santos
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
authors.forename: José R
authors.initials: JR
authors.lastname: Ascenso
authors.forename: M
authors.initials: M
authors.lastname: João Ferreira
authors.forename: António
authors.initials: A
authors.lastname: Paulo
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002614:Chelating Agents / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D005260:Female; D005708:Gallium / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism*; D014961:X-Ray Diffraction
chemical_list: D015415:Biomarkers; D002614:Chelating Agents; D009942:Organometallic Compounds; D005708:Gallium