Responsive Shift Probes for Magnetic Resonance

Abstract

Magnetic resonance chemical shift imaging can provide chemical information about biological tissue. However, 1H MR shift imaging in vivo is a much less exploited technique than standard MRI, due to the presence of strong NMR signals from water and fat. Paramagnetic lanthanide(III) complexes, in which a tert-butyl reporter group is incorporated, can be used to shift a proton resonance ±80 ppm from the water signal allowing selective observation. The proximity of the paramagnetic lanthanide(III) ion enhances the longitudinal relaxation rates of the surrounding nuclei, permitting faster data acquisition per unit time.

The chemical shifts of paramagnetically shifted proton resonances, within kinetically stable macrocyclic lanthanide(III) complexes, inherently encode temperature information. The introduction of a phosphonate group adjacent to the tert-butyl reporter group introduces pH responsive behaviour. The dual sensitivity of such probes has allowed the simultaneous triple imaging of the water signal and the shifted tert butyl signals of thulium(III) and dysprosium(III) complexes of a common ligand, separated by over 160 ppm. Spectral imaging experiments in vivo allow the pH and temperature of the liver, kidney and bladder to be measured within a mouse model. Further modification of the ligand structure changes the biodistribution profile of the complex whilst maintaining and even improving the chemical shift and relaxation rates of the probe.

In-depth structural and NMR analysis of a series of lanthanide complexes based on different ligand motifs has demonstrated that the MR properties of a paramagnetic complex cannot be readily predicted using the longstanding theories of shift and relaxation. Seemingly small modifications to ligand structure can significantly alter the size, magnitude, sign and orientation of the magnetic susceptibility tensor.

Finally, introduction of a specific zinc(II) ion chelating agent adjacent to the tert-butyl reporter group has created the first zinc(II) responsive paramagnetic probe for proton magnetic resonance spectroscopy. The strong and selective binding of zinc(II) was shown to be reversible.