title: Synthesis and characterisation of bismacrocyclic DO3A-amide derivatives - an approach towards metal-responsive PARACEST agents.
abstract: Three new bismacrocyclic Ln(3+) chelates consisting of triamide derivatives of cyclen with glycine, methyl and tert-butyl substituents (, respectively) linked to an acyclic EGTA-derived calcium chelator were synthesised as potential MRI contrast agents (EGTA - ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid). Eu(3+) and Yb(3+) complexes of were investigated as chemical exchange saturation transfer (CEST) agents. Moderate to minor CEST effects were observed for , and complexes in the absence of Ca(2+), with negligible changes upon addition of this metal ion. Luminescence steady-state emission and lifetime experiments did not reveal any changes in the coordination environment of the complexes, while the number of inner-sphere water molecules remained constant in the absence and presence of Ca(2+). The protonation constants of and and stability constants of their complexes with Ca(2+), Mg(2+) and Zn(2+) were determined by means of potentiometric titrations. The results show that the charge of the complex dramatically affects the protonation constants of the EGTA-binding unit. The stability constants of the complexes formed with Ca(2+), Mg(2+) and Zn(2+) are several orders of magnitude lower than those of EGTA. These findings indicate that the nature of Ln(3+) chelates and their charge are the main reasons for the observed results and weaker response of these EGTA-derived triamide derivatives compared to their tricarboxylate analogues.
authors.affiliation: MR Neuroimaging Agents, Max Planck Institute for Biological Cybernetics, Spemannstr. 41, 72076 Tübingen, Germany. goran.angelovski@tuebingen.mpg.de.
authors.forename: Nevenka
authors.initials: N
authors.lastname: Cakić
authors.affiliation: Department of Analytical Chemistry, Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.
authors.forename: Tatjana Ž
authors.initials: TŽ
authors.lastname: Verbić
authors.affiliation: Faculty of Medicinal Science, University of Kragujevac, S. Markovića 69, 34000 Kragujevac, Serbia.
authors.forename: Ratomir M
authors.initials: RM
authors.lastname: Jelić
authors.affiliation: Centro de Investigaciones Científicas Avanzadas (CICA) and Departamento de Química Fundamental, Universidade da Coruña, Campus da Zapateira, Rúa da Fraga 10, 15008 A Coruña, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Platas-Iglesias
authors.affiliation: MR Neuroimaging Agents, Max Planck Institute for Biological Cybernetics, Spemannstr. 41, 72076 Tübingen, Germany. goran.angelovski@tuebingen.mpg.de.
authors.forename: Goran
authors.initials: G
authors.lastname: Angelovski
mesh_terms: D000577:Amides / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D028581:Lanthanoid Series Elements / Q000737:chemistry*; D047028:Macrocyclic Compounds / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D000577:Amides; D003287:Contrast Media; D006573:Heterocyclic Compounds, 1-Ring; D028581:Lanthanoid Series Elements; D047028:Macrocyclic Compounds; D009942:Organometallic Compounds; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid