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

Abstract

The design and synthesis of hydrazone-based switches with a CF 3 reporting group for 19 F pH imaging using relaxation rate changes were described. A paramagnetic center was introduced into the hydrazone molecular switch scaffold by substitution of an ethyl functional group with a paramagnetic complex. The mechanism of 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 distance between fluorine atoms and the paramagnetic center. Among the three possible variants of the ligand, the meta isomer was found to offer the highest potential changes in relaxation rates due to the significant paramagnetic relaxation enhancement (PRE) effect and a stable position of the 19 F signal, allowing for the tracking of a single narrow 19 F resonance for imaging purposes. The selection of the most suitable Gd(III) paramagnetic ion for complexation was conducted by theoretical calculations based on the Bloch−Redfield−Wangsness (BRW) theory, taking into account the electron−nucleus dipole−dipole and 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 transition between E and Z−H + isomers. The results demonstrate the potential of this approach for pH imaging using relaxation rate changes instead of chemical shift.