CONSPECTUS: Future medicine is primarily aiming at the development of novel approachesfor an early diagnosis of diseases and a personalized therapy for patients. For achieving theseobjectives, a key role is played by ...CONSPECTUS: Future medicine is primarily aiming at the development of novel approachesfor an early diagnosis of diseases and a personalized therapy for patients. For achieving theseobjectives, a key role is played by medical imaging. Among available noninvasive imagingtechniques, Fluorine-19 (^(19)F) Magnetic Resonance Imaging (MRI) is emerging as a powerfulquantitative detection modality for clinical use both for molecular imaging and for cell tracking.The strength of using ^(19)F-MRI is mainly related to the lack of endogenous organic fluorine intissues, with no background, enabling the visualization of fluorinated tracers as hot-spot images,adding secondary independent information to the anatomical features provided by thegrayscale ^(1)H-MRI. The main challenge for ^(19)F-MRI clinical application is the intrinsic reducedsensitivity of MRI. To improve sensitivity, undoubtedly the use of a high field MRI scanner andcryogenic radiofrequency probes is advantageous, but there is a clear need of developingincreasingly effective fluorinated tracers.The ideal tracer should bear as many as possible magnetically equivalent fluorine atoms andshow optimal magnetic resonance relaxivity properties (i.e., T_(1) and T_(2)), which enable reduced acquisition time with the possibility toapply fast imaging methods. Moreover, it should be biocompatible with reduced tendency to bioaccumulate in tissues, which is oneof the main drawbacks in using perfluorocarbons (PFCs), together with their difficulty to be chemically modified with functionalgroups. 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 ^(19)F-MRI preclinical and clinical studies, with the above-mentioned limitations. In thisregard, molecules bearing short branched fluorinated chains gained a lot of attention for their high number of equivalent fluorinesand expected capability of reducing bioaccumulation concerns. A valuable building block for branched fluorinated tracers isperfluoro-tert-butanol (PFTB), with nine magnetically equivalent fluorines and easy availability and modification.In this Account we will discuss the main challenges that ^(19)F-MRI has to overcome for increasing its clinical use, highlighting on onehand the need of developing customized fluorinated materials for increasing sensitivity and enabling multimodal properties, and onthe other hand, the importance of the ultrastructure of the final formulation for the final biological response (i.e., clearance). In thiscontext, our group has been focusing on the synthesis and development of branched fluorinated tracers, for which the originator is amolecule called PERFECTA (from suPERFluorinatEdContrasT Agent), bearing 36 equiv ^(19)F atoms, which showed not only optimalrelaxometry properties but also a very specific and intense Raman signal. Thus, PERFECTA and its derivatives represent a newfamily of multimodal tracers enabling multiscale analysis, from whole body imaging (^(19)F-MRI) to microscopic detection at thecellular/tissue level (Raman microscopy). We believe that our proposed PFTB strategy can strongly promote the production ofincreasingly effective ^(19)F-MRI materials with additional functionalities, facilitating the clinical translation of this imaging modality.展开更多
基金the NEWMED project,ID:1175999(funded by Regione Lombardia POR FESR 20142020)F.B.B.and P.M.are also thankful to the project NiFTy funded by MIUR(PRIN2017,no.2017MYBTXC)+1 种基金C.C.,V.D.,and F.B.B.are also thankful to the P2RY12 project,ID:GR-2016-02361325(funded by the Italian Ministry of Health)O.K.acknowledges the Alexander von Humboldt Foundation.The figures were made using BioRender.com.
文摘CONSPECTUS: Future medicine is primarily aiming at the development of novel approachesfor an early diagnosis of diseases and a personalized therapy for patients. For achieving theseobjectives, a key role is played by medical imaging. Among available noninvasive imagingtechniques, Fluorine-19 (^(19)F) Magnetic Resonance Imaging (MRI) is emerging as a powerfulquantitative detection modality for clinical use both for molecular imaging and for cell tracking.The strength of using ^(19)F-MRI is mainly related to the lack of endogenous organic fluorine intissues, with no background, enabling the visualization of fluorinated tracers as hot-spot images,adding secondary independent information to the anatomical features provided by thegrayscale ^(1)H-MRI. The main challenge for ^(19)F-MRI clinical application is the intrinsic reducedsensitivity of MRI. To improve sensitivity, undoubtedly the use of a high field MRI scanner andcryogenic radiofrequency probes is advantageous, but there is a clear need of developingincreasingly effective fluorinated tracers.The ideal tracer should bear as many as possible magnetically equivalent fluorine atoms andshow optimal magnetic resonance relaxivity properties (i.e., T_(1) and T_(2)), which enable reduced acquisition time with the possibility toapply fast imaging methods. Moreover, it should be biocompatible with reduced tendency to bioaccumulate in tissues, which is oneof the main drawbacks in using perfluorocarbons (PFCs), together with their difficulty to be chemically modified with functionalgroups. 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 ^(19)F-MRI preclinical and clinical studies, with the above-mentioned limitations. In thisregard, molecules bearing short branched fluorinated chains gained a lot of attention for their high number of equivalent fluorinesand expected capability of reducing bioaccumulation concerns. A valuable building block for branched fluorinated tracers isperfluoro-tert-butanol (PFTB), with nine magnetically equivalent fluorines and easy availability and modification.In this Account we will discuss the main challenges that ^(19)F-MRI has to overcome for increasing its clinical use, highlighting on onehand the need of developing customized fluorinated materials for increasing sensitivity and enabling multimodal properties, and onthe other hand, the importance of the ultrastructure of the final formulation for the final biological response (i.e., clearance). In thiscontext, our group has been focusing on the synthesis and development of branched fluorinated tracers, for which the originator is amolecule called PERFECTA (from suPERFluorinatEdContrasT Agent), bearing 36 equiv ^(19)F atoms, which showed not only optimalrelaxometry properties but also a very specific and intense Raman signal. Thus, PERFECTA and its derivatives represent a newfamily of multimodal tracers enabling multiscale analysis, from whole body imaging (^(19)F-MRI) to microscopic detection at thecellular/tissue level (Raman microscopy). We believe that our proposed PFTB strategy can strongly promote the production ofincreasingly effective ^(19)F-MRI materials with additional functionalities, facilitating the clinical translation of this imaging modality.
