Chiral lanthanide complexes as probes for bioactive species
In vivo detection of lactate by (^1)H MRS is of prime importance in the diagnosis, grading and therapeutic monitoring of pathological states such as cancer, stroke and heart disease. However, the detection of this metabolite is affected by the limits of the MRS technique, such as the low sensitivity, and the overlapping resonances of lactate with other biological species. A solution to the problem is to envisage the use of a paramagnetic metal chelate system, acting as a shift and relaxation agent, in order to affect spectral resolution and also to allow rapid acquisition times to be implemented, giving increased signal intensity. For an effective shift reagent the binding to lactate should be reversible and in fast exchange on the NMR timescale. A single isomer in solution is preferred, in order to simplify the interpretation of the spectra, and a large lanthanide induced shift is necessary to avoid any overlapping of biological background signals with the resonances of interest. Moreover, water-soluble, kinetically stable complexes are required for use ш vivo. With these features in mind, several enantiopure heptadentate lanthanide complexes have been designed, and their ability to bind selectively and reversibly to lactate has been investigated. In order to achieve the fast exchange conditions required, the binding affinity and selectivity for lactate have been modulated by varying the Ln(^3+) ion and the ligand structure, in particular the peripheral electrostatic charge of the complex (i.e. anionic vs. neutral) and the local charge and steric demand at the metal centre. The binding of lactate to these novel chiral, heptadentate lanthanide complexes has been effectively signalled by (^1)Ή NMR (Yb(^3+)), emission spectroscopy (Eu(^3+)), hydration state studies (Tb(^3+)and circular dichroism (Yb(^3+)). These spectroscopic and chiroptical techniques have also been employed to investigate the binding of such complexes to several biological anions in aqueous media, with the aim of assessing the potential of such systems as effective NMR, luminescent and chiroptical probes for a wider range of bioactive species.