Ln(III)-complexes of a DOTA analogue with an ethylenediamine pendant arm as pH-responsive PARACEST contrast agents

A novel macrocyclic DO3A derivative containing a linear diamine pendant arm, H(3)do3aNN, was prepared and its protonation and complexation properties were studied by means of potentiometry. It determined ligand consecutive protonation constants log K-An = 12.62, 10.28, 9.67, 8.30, 3.30 and 1.58 and stability constants of selected lanthanide (Eu(III), Yb(III)) complexes log K-EuL = 23.16 and log K-YbL = 22.76. The complexes could be protonated on the pendant amino group(s) with log K(HLM) approximate to 5.6 and log K(H2LM) approximate to 4.8. Solution structures of both complexes were studied by NMR spectroscopy. The study revealed that the complex species exist exclusively in the form of twisted-square-antiprismatic (TSA) isomers. The complexes show significant pH dependence of the Chemical Exchange Saturation Transfer (CEST) between their amino groups and the bulk water molecules in the pH range of 5-8. Thus, the pH dependence of the magnetization transfer ratio of CEST signals can be used for pH determination using magnetic resonance imaging techniques in a pH range relevant for in vivo conditions.