Hydrazone-based molecular switches serve as efficient ratiometric pH-sensitive agents that can be tracked with 19F NMR/MRI and 1H NMR. Structural changes induced between pH 3 and 4 lead to signal appearance and disappearance at 1H and 19F NMR spectra allowing ratiometric pH measurements. The most pronounced are resonances of the CF3 group shifted by 1.8 ppm with 19F NMR and a hydrazone proton shifted by 2 ppm with 1H NMR.

Magnetic resonance imaging (MRI) is one of the most powerful imaging tools today, capable of displaying superior soft‐tissue contrast. This review discusses developments in the field of 19F MRI multimodal probes in combination with optical fluorescence imaging (OFI), 1H MRI, chemical exchange saturation transfer (CEST) MRI, ultrasonography (USG), X‐ray computed tomography (CT), single photon emission tomography (SPECT), positron emission tomography (PET), and photoacoustic imaging (PAI). In each case, multimodal 19F MRI probes compensate for the deficiency of individual techniques and offer improved sensitivity or accuracy of detection over unimodal counterparts. Strategies for designing 19F MRI multimodal probes are described with respect to their structure, physicochemical properties, biocompatibility, and the quality of images.

19 F magnetic resonance imaging (MRI) is a promising tool in medical diagnostics. An important class of 19 F MRI contrast agents is based on paramagnetic resonance enhancement. This effect allows an improvement in sensitivity by increasing the number of scans per unit of time or facilitates the development of responsive contrast agents that are based on changes in relaxation rates as a detection principle. In this work, Bloch− Redfield−Wangsness relaxation theory was used to predict the relaxation properties of existing lanthanoid and transition metal complexes of fluoroorganic ligands and to evaluate several design strategies for responsive contrast agents. Electron−nucleus dipole−dipole, Curie relaxation, and contact interactions were included in the model. Potential significance of chemical shift anisotropy−anisotropic dipolar shielding cross-correlation was discussed. The calculated and experimental results were well aligned. The presented model, along with the optimized field-dependent values of electronic relaxation times, could be used for the preliminary selection of the optimal metal ion for applications in 19 F MRI. The results indicate potential advantages of other metal ions in addition to Gd 3+ particularly Cu 2+ , Mn 2+ , Ni 2+ , Fe 3+ , and other lanthanoids as a part of 19 F contrast agents.

This review focuses on multimodal imaging encompassing 19F MRI (magnetic resonance imaging) as one of the modalities. Structure of the probes and example applications in optical fluorescence imaging (OFI), 1H MRI, chemical exchange saturation transfer (CEST), MRI, ultrasonography (USG), X‐ray computed tomography (CT), single‐photon emission tomography (SPECT), positron emission tomography (PET), and photoacoustic imaging (PAI) as well as other less popular techniques were discussed. For more information, see the Review by D. Janasik and T. Krawczyk on page 4–35.

19F MRI is a promising method of diagnosis that can complement the commonly used 1H MRI with gadolinium contrast agents. Copolymers containing fluoroorganic groups demonstrate many advantages as potential 19F MRI contrast agents. In this work, a series of copolymers based on 2,2,2‐trifluoroethyl methacrylate (TFEMA), 1,1,1,3,3,3‐hexafluoroisopropyl methacrylate (HFiPMA), 2‐(dimethylamino)ethyl methacrylate (DMAEMA), or 2‐hydroxyethyl methacrylate (HEMA) units are prepared using atom transfer radical polymerization. The highest S/N values in a 19F NMR spectra is achieved with a copolymer containing 15–25 wt% TFEMA or 18–22 wt% HFiPMA. Copolymers of HFiPMA show a strong effect of pH on T1 and T2 relaxation times while only T2 is significantly affected for the TFEMA copolymers. DFT calculations reveal that the phenomenon is most likely caused by the pH‐induced changes in the distance of fluoroorganic groups within a polymer chain.

Molecular switches have become an area of great interest in recent years. They are explored as high-density data storage and organic diodes in molecular electronics as well as chemosensors due to their ability to undergo a transition between well-defined structures under the action of external stimuli. One of the types of such switches is hydrazones. They work by changing the configuration from E to Z under the influence of pH or light. The change in configuration is accompanied by a change in the absorption band and changes in the nuclear magnetic resonance (NMR) spectrum. In this publication, the structure–property relationship of fluorinated hydrazone switches was established. A linear relationship between the Hammett substituent constants and the pH where the switching occurs was found. Introduction of strong electron-donating groups allowed obtaining a hydrazone switch of pK a = 6 suitable for application in 19F MRI as contrast agents.

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.