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

[Abstract] Three new bismacrocyclic Ln3+ chelates consisting of triamide derivatives of cyclen with glycine, methyl and tert-butyl substituents (L1–3, 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). Eu3+ and Yb3+ complexes of L1–3 were investigated as chemical exchange saturation transfer (CEST) agents. Moderate to minor CEST effects were observed for Eu2L1, Eu2L2 and Yb2L2 complexes in the absence of Ca2+, 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 Ca2+. The protonation constants of Eu2L1 and Eu2L2 and stability constants of their complexes with Ca2+, Mg2+ and Zn2+ 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 Ca2+, Mg2+ and Zn2+ are several orders of magnitude lower than those of EGTA. These findings indicate that the nature of Ln3+ 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