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Theranostic imaging methods could greatly enhance our understanding of the distribution of CNS-acting drugs in individual patients. Fluorine-19 magnetic resonance imaging ( 19 F MRI) offers the opportunity to localize and quantify fluorinated drugs non-invasively, without modifications and without the application of ionizing or other harmful radiation. Here we investigated siponimod, a sphingosine 1-phosphate (S 1 P) receptor antagonist indicated for secondary progressive multiple sclerosis (SPMS), to determine the feasibility of in vivo 19 F MR imaging of a disease modifying drug. Methods: The 19 F MR properties of siponimod were characterized using spectroscopic techniques. Four MRI methods were investigated to determine which was the most sensitive for 19 F MR imaging of siponimod under biological conditions. We subsequently administered siponimod orally to 6 mice and acquired 19 F MR spectra and images in vivo directly after administration, and in ex vivo tissues. Results: The 19 F transverse relaxation time of siponimod was 381 ms when dissolved in dimethyl sulfoxide, and substantially reduced to 5 ms when combined with serum, and to 20 ms in ex vivo liver tissue. Ultrashort echo time (UTE) imaging was determined to be the most sensitive MRI technique for imaging siponimod in a biological context and was used to map the drug in vivo in the stomach and liver. Ex vivo images in the liver and brain showed an inhomogeneous distribution of siponimod in both organs. In the brain, siponimod accumulated predominantly in the cerebrum but not the cerebellum. No secondary 19 F signals were detected from metabolites. From a translational perspective, we found that acquisitions done on a 3.0 T clinical MR scanner were 2.75 times more sensitive than acquisitions performed on a preclinical 9.4 T MR setup when taking changes in brain size across species into consideration and using equivalent relative spatial resolution. Conclusion: Siponimod can be imaged non-invasively using 19 F UTE MRI in the form administered to MS patients, without modification. This study lays the groundwork for more extensive preclinical and clinical investigations. With the necessary technical development, 19 F MRI has the potential to become a powerful theranostic tool for studying the time-course and distribution of CNS-acting drugs within the brain, especially during pathology., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Kidney-associated pathologies would greatly benefit from noninvasive and robust methods that can objectively quantify changes in renal function. In the past years there has been a growing incentive to develop new applications for fluorine ( 19 F) MRI in biomedical research to study functional changes during disease states. 19 F MRI represents an instrumental tool for the quantification of exogenous 19 F substances in vivo. One of the major benefits of 19 F MRI is that fluorine in its organic form is absent in eukaryotic cells. Therefore, the introduction of exogenous 19 F signals in vivo will yield background-free images, thus providing highly selective detection with absolute specificity in vivo. Here we introduce the concept of 19 F MRI, describe existing challenges, especially those pertaining to signal sensitivity, and give an overview of preclinical applications to illustrate the utility and applicability of this technique for measuring renal function in animal models.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by two separate chapters describing the experimental procedure and data analysis.

Fluorine-19 MRI shows great promise for a wide range of applications including renal imaging, yet the typically low signal-to-noise ratios and sparse signal distribution necessitate a thorough data preparation.This chapter describes a general data preparation workflow for fluorine MRI experiments. The main processing steps are: (1) estimation of noise level, (2) correction of noise-induced bias and (3) background subtraction. The protocol is supplemented by an example script and toolbox available online.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This analysis protocol chapter is complemented by two separate chapters describing the basic concept and experimental procedure.

Purpose: To examine the performance of compressed sensing (CS) in reconstructing low signal-to-noise ratio (SNR) 19 F MR signals that are close to the detection threshold and originate from small signal sources with no a priori known location., Methods: Regularization strength was adjusted automatically based on noise level. As performance metrics, root-mean-square deviations, true positive rates (TPRs), and false discovery rates were computed. CS and conventional reconstructions were compared at equal measurement time and evaluated in relation to high-SNR reference data. 19 F MR data were generated from a purpose-built phantom and benchmarked against simulations, as well as from the experimental autoimmune encephalomyelitis mouse model. We quantified the signal intensity bias and introduced an intensity calibration for in vivo data using high-SNR ex vivo data., Results: Low-SNR 19 F MR data could be reliably reconstructed. Detection sensitivity was consistently improved and data fidelity was preserved for undersampling and averaging factors of α = 2 or = 3. Higher α led to signal blurring in the mouse model. The improved TPRs at α = 3 were comparable to a 2.5-fold increase in measurement time. Whereas CS resulted in a downward bias of the 19 F MR signal, Fourier reconstructions resulted in an unexpected upward bias of similar magnitude. The calibration corrected signal-intensity deviations for all reconstructions., Conclusion: CS is advantageous whenever image features are close to the detection threshold. It is a powerful tool, even for low-SNR data with sparsely distributed 19 F signals, to improve spatial and temporal resolution in 19 F MR applications., (© 2020 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Objective: This study examines the influence of the environmental factor temperature on the 19 F NMR characteristics of fluorinated compounds in phantom studies and in tissue., Materials and Methods: 19 F MR mapping and MR spectroscopy techniques were used to characterize the 19 F NMR characteristics of perfluoro-crown ether (PFCE), isoflurane, teriflunomide, and flupentixol. T 1 and T 2 mapping were performed, while temperature in the samples was changed (T = 20-60 °C) and monitored using fiber optic measurements. In tissue, T 1 of PFCE nanoparticles was determined at physiological temperatures and compared with the T 1- measured at room temperature., Results: Studies on PFCE, isoflurane, teriflunomide, and flupentixol showed a relationship between temperature and their physicochemical characteristics, namely, chemical shift, T 1 and T 2 . T 1 of PFCE nanoparticles was higher at physiological body temperatures compared to room temperature., Discussion: The impact of temperature on the 19 F NMR parameters of fluorinated compounds demonstrated in this study not only opens a trajectory toward 19 F MR-based thermometry, but also indicates the need for adapting MR sequence parameters according to environmental changes such as temperature. This will be an absolute requirement for detecting fluorinated compounds by 19 F MR techniques in vivo.

Objective: Fluorine MR would benefit greatly from enhancements in signal-to-noise ratio (SNR). This study examines the sensitivity gain of 19 F MR that can be practically achieved when moving from 9.4 to 21.1 T., Materials and Methods: We studied perfluoro-15-crown-5-ether (PFCE) at both field strengths (B 0 ), as a pure compound, in the form of nanoparticles (NP) as employed to study inflammation in vivo, as well as in inflamed tissue. Brains, lymph nodes (LNs) and spleens were obtained from mice with experimental autoimmune encephalomyelitis (EAE) that had been administered PFCE NPs. All samples were measured at both B 0 with 2D-RARE and 2D-FLASH using 19 F volume radiofrequency resonators together. T 1 and T 2 of PFCE were measured at both B 0 strengths., Results: Compared to 9.4 T, an SNR gain of > 3 was observed for pure PFCE and > 2 for PFCE NPs at 21.1 T using 2D-FLASH. A dependency of 19 F T 1 and T 2 relaxation on B 0 was demonstrated. High spatially resolved 19 F MRI of EAE brains and LNs at 21.1 T revealed signals not seen at 9.4 T., Discussion: Enhanced SNR and T 1 shortening indicate the potential benefit of in vivo 19 F MR at higher B 0 to study inflammatory processes with greater detail.

Neuroinflammation can be monitored using fluorine-19 ( 19 F)-containing nanoparticles and 19 F MRI. Previously we studied neuroinflammation in experimental autoimmune encephalomyelitis (EAE) using room temperature (RT) 19 F radiofrequency (RF) coils and low spatial resolution 19 F MRI to overcome constraints in signal-to-noise ratio (SNR). This yielded an approximate localization of inflammatory lesions. Here we used a new 19 F transceive cryogenic quadrature RF probe ( 19 F-CRP) that provides the SNR necessary to acquire superior spatially-resolved 19 F MRI. First we characterized the signal-transmission profile of the 19 F-CRP. The 19 F-CRP was then benchmarked against a RT 19 F/ 1 H RF coil. For SNR comparison we used reference compounds including 19 F-nanoparticles and ex vivo brains from EAE mice administered with 19 F-nanoparticles. The transmit/receive profile of the 19 F-CRP diminished with increasing distance from the surface. This was counterbalanced by a substantial SNR gain compared to the RT coil. Intraparenchymal inflammation in the ex vivo EAE brains was more sharply defined when using 150 μm isotropic resolution with the 19 F-CRP, and reflected the known distribution of EAE histopathology. At this spatial resolution, most 19 F signals were undetectable using the RT coil. The 19 F-CRP is a valuable tool that will allow us to study neuroinflammation with greater detail in future in vivo studies.