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

Nevenka Cakić, Tatjana Ž. Verbić, Ratomir M. Jelić, Carlos Platas-Iglesias, Goran Angelovski

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.