Hydrazone Molecular Switches with Paramagnetic Center as 19F Magnetic Resonance Imaging Relaxation Enhancement Agents for pH Imaging

Thedesign and synthesisof hydrazone-based switches with a CF3 reporting groupfor F-19 pH imaging using relaxationrate changes were described. A paramagnetic center was introducedinto the hydrazone molecular switch scaffold by substitution of anethyl functional group with a paramagnetic complex. The mechanismof activation relies on a gradual increase in T (1) and T (2) magnetic resonance imaging(MRI) relaxation times as pH decreases due to E/Z isomerization, which results in a change in the distancebetween fluorine atoms and the paramagnetic center. Among the threepossible variants of the ligand, the meta isomer was found to offerthe highest potential changes in relaxation rates due to the significantparamagnetic relaxation enhancement (PRE) effect and a stable positionof the F-19 signal, allowing for the tracking of a singlenarrow F-19 resonance for imaging purposes. The selectionof the most suitable Gd-(III) paramagnetic ion for complexation wasconducted by theoretical calculations based on the Bloch-Redfield-Wangsness(BRW) theory, taking into account the electron-nucleus dipole-dipoleand Curie interactions only. The results were verified experimentally,confirming the accuracy of theoretical predictions, good solubility,and stability of the agents in water and the reversible transitionbetween E and Z-H+ isomers. The results demonstratethe potential of this approach for pH imaging using relaxation ratechanges instead of chemical shift.