A Pyrophosphate-Responsive Gadolinium(III) MRI Contrast Agent

Graphical Abstract

Pick an anion: The anion-binding properties of functionalised Ln-DTPA-bis-amide complexes (Ln=Gd³⁺, Eu³⁺, DTPA=diethylene triamine pentaacetic acid) were investigated by using indicator displacement assays (IDAs) (see picture). A remarkable selectivity for polyphosphorylated species was observed. This has been successfully used to modulate the relaxivity of the Gd³⁺ complex with pyrophosphate.

Abstract

This study shows that the relaxivity and optical properties of functionalised lanthanide-DTPA-bis-amide complexes (lanthanide=Gd³⁺ and Eu³⁺, DTPA=diethylene triamine pentaacetic acid) can be successfully modulated by addition of specific anions, without direct Ln³⁺/anion coordination. Zinc(II)-dipicolylamine moieties, which are known to bind strongly to phosphates, were introduced in the amide “arms” of these ligands, and the interaction of the resulting Gd–Zn₂ complexes with a range of anions was screened by using indicator displacement assays (IDAs). Considerable selectivity for polyphosphorylated species (such as pyrophosphate and adenosine-5′-triphosphate (ATP)) over a range of other anions (including monophosphorylated anions) was apparent. In addition, we show that pyrophosphate modulates the relaxivity of the gadolinium(III) complex, this modulation being sufficiently large to be observed in imaging experiments. To establish the binding mode of the pyrophosphate and gain insight into the origin of the relaxometric modulation, a series of studies including UV/Vis and emission spectroscopy, luminescence lifetime measurements in H₂O and D₂O, ¹⁷O and ³¹P NMR spectroscopy and nuclear magnetic resonance dispersion (NMRD) studies were carried out.