Small structural change, major functional impact: a new Ln(III)(HP-DO3A) derivative for MRI lactate sensing

Ln(III) complexes with octa-coordinating macrocyclic ligands are candidates of choice for the design of MRI contrast agents either as relaxation enhancers or CEST agents. Among them, HP-DO3A is under intense scrutiny as minor structural changes have been shown to markedly affect the properties of the corresponding Ln(iii) complexes. In this work, we report our observations on Ln(iii) complexes of HnP-DO3A, an isomer of HP-DO3A, with a 3-hydroxypropyl moiety in place of a 2-hydroxypropyl one. When Ln = Gd, the change in the structure of the ligand results in a markedly faster exchange of the coordinated water molecule and in a slightly higher relaxivity that lacks the well-established hump at basic pH values observed for Gd(HP-DO3A). Moreover, Gd(HnP-DO3A) shows a good propensity to form ternary complexes with endogenous anions as well as a detectable binding ability with exposed functionalities on the surface of serum proteins. Remarkably, the in vitro standard test indicates an increase in kinetic inertness upon formation of the ternary complex in the presence of an excess of lactate anions. Furthermore, Yb(HnP-DO3A) was found to be an excellent CEST agent that responds well to lactate concentration. The Z-spectra of aqueous solutions of this complex with varying amounts of lactate showed characteristic ST% absorptions for the coordinated hydroxyl group (94 ppm) and for the lactate anion (254 ppm), as expected from the observations made by high-resolution 1H-NMR spectroscopy. By taking the ratio of the two ST% values, one can remove the need to know the concentration of the complex and get a quantitative estimation of the lactate anion.