Synthesis and characterisation of bismacrocyclic DO3A-amide derivatives an approach towards metal-responsive PARACEST agents

• Published in: Dalton transactions : an international journal of inorganic chemistry 2016-04, Vol.45 (15), p.6555-6565
• Main Authors: Caki, Nevenka, Verbi, Tatjana, Jeli, Ratomir M, Platas-Iglesias, Carlos, Angelovski, Goran
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Charge; Chelates; Chemistry Techniques, Synthetic; Constants; Contrast agents; Contrast Media - chemical synthesis; Contrast Media - chemistry; Derivatives; Ethylene; Heterocyclic Compounds, 1-Ring - chemistry; Lanthanoid Series Elements - chemistry; Macrocyclic Compounds - chemistry; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Protonation; Stability constants
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/c5dt04625d

Three new bismacrocyclic Ln 3+ chelates consisting of triamide derivatives of cyclen with glycine, methyl and tert -butyl substituents ( L 13 , 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 L 13 were investigated as chemical exchange saturation transfer (CEST) agents. Moderate to minor CEST effects were observed for Eu 2 L 1 , Eu 2 L 2 and Yb 2 L 2 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 Eu 2 L 1 and Eu 2 L 2 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. Three bismacrocyclic amide derivatives bearing two types of chelating moieties were prepared. The properties of their lanthanide complexes in the absence and presence of calcium, magnesium or zinc ions were studied.