Multibranched-Based Fluorinated Materials: Tailor-Made Design of ¹⁹F-MRI Probes

Abstract

Conspectus Future medicine is primarily aiming at the development of novel approaches for an early diagnosis of diseases and a personalized therapy for patients. For achieving these objectives, a key role is played by medical imaging. Among available noninvasive imaging techniques, Fluorine-19 (19F) Magnetic Resonance Imaging (MRI) is emerging as a powerful quantitative detection modality for clinical use both for molecular imaging and for cell tracking. The strength of using 19F-MRI is mainly related to the lack of endogenous organic fluorine in tissues, with no background, enabling the visualization of fluorinated tracers as hot-spot images, adding secondary independent information to the anatomical features provided by the grayscale 1H-MRI. The main challenge for 19F-MRI clinical application is the intrinsic reduced sensitivity of MRI. To improve sensitivity, undoubtedly the use of a high field MRI scanner and cryogenic radiofrequency probes is advantageous, but there is a clear need of developing increasingly effective fluorinated tracers. The ideal tracer should bear as many as possible magnetically equivalent fluorine atoms and show optimal magnetic resonance relaxivity properties (i.e., T 1 and T 2), which enable reduced acquisition time with the possibility to apply fast imaging methods. Moreover, it should be biocompatible with reduced tendency to bioaccumulate in tissues, which is one of the main drawbacks in using perfluorocarbons (PFCs), together with their difficulty to be chemically modified with functional groups. In fact, PFCs such as perfluorooctyl bromide (PFOB), perfluoro-15-crown-5-ether (PFCE), and linear perfluoropolyethers (PFPE) are currently the most used tracers in 19F-MRI preclinical and clinical studies, with the above-mentioned limitations. In this regard, molecules bearing short branched fluorinated chains gained a lot of attention for their high number of equivalent fluorines and expected capability of reducing bioaccumulation concerns. A valuable building block for branched fluorinated tracers is perfluoro-tert-butanol (PFTB), with nine magnetically equivalent fluorines and easy availability and modification. In this Account we will discuss the main challenges that 19F-MRI has to overcome for increasing its clinical use, highlighting on one hand the need of developing customized fluorinated materials for increasing sensitivity and enabling multimodal properties, and on the other hand, the importance of the ultrastructure of the final formulation for the final biological response (i.e., clearance). In this context, our group has been focusing on the synthesis and development of branched fluorinated tracers, for which the originator is a molecule called PERFECTA (from suPERFluorinatEdContrasT Agent), bearing 36 equiv 19F atoms, which showed not only optimal relaxometry properties but also a very specific and intense Raman signal. Thus, PERFECTA and its derivatives represent a new family of multimodal tracers enabling multiscale analysis, from whole body imaging (19F-MRI) to microsco...

Transition metal complexes of cyclam with two 2,2,2-trifluoroethylphosphinate pendant arms as probes for 19F magnetic resonance imaging

“…in monitoring the fate of transplanted cells (cell tracking). [6][7][8] A number of compounds have been tested as 19 F NMR contrast agents. They were usually perfluorinated hydrocarbons † Electronic supplementary information (ESI) available: NMR spectra of studied complexes, colour change of isomeric Cu(II) complexes, experimental data and details for the crystal structure refinement, ligand distribution diagram, details of the kinetic inertness study, NMR characterization of organic compounds, and discussion of the crystal structures of synthetic intermediates.…”

“…in monitoring the fate of transplanted cells (cell tracking). [6][7][8] A number of compounds have been tested as 19 F NMR contrast agents. They were usually perfluorinated hydrocarbons and their derivatives (for simplicity, they are called perfluorocarbons, PFCs), and some of them have been already studied for a long time as potential blood substitutes.…”

Biodegradable polyphosphoester micelles act as both background-free 31P magnetic resonance imaging agents and drug nanocarriers

“…Lastly, due to the high chemical stability which makes PFAS basically undegradable, they are classified as environmental pollutants 15 . Current approaches focus on improving the properties of fluorinated compounds for 19 F MRI, e. g. developing of partly fluorinated polymers which are stable in physiological milieu, or inorganic nanoparticles 13,[18][19][20][21][22][23][24][25] . Instead, we decided to develop polymers that can be imaged via 31 P nuclei in their backbone instead of common 19 F, to take advantage of the biocompatible properties of polyphosphoesters 26,27 .…”