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 (L^1–3, 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 L^1–3 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.