B<sub>1</sub>inhomogeneity correction of RARE MRI at low SNR: Quantitative in vivo<sup>19</sup>F MRI of mouse neuroinflammation with a cryogenically‐cooled transceive surface radiofrequency probe

Delgado, Paula Ramos; Kuehne, André; Aravina, Mariya; Millward, Jason M.; Vazquez, A. Villa; Starke, Ludger; Waiczies, Helmar; Pohlmann, Andreas; Niendorf, Thoralf; Waiczies, Sonia

doi:10.1002/mrm.29094

Cited by 5 publications

(2 citation statements)

References 54 publications

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“…Naturally occurring fluorine is 100% the 19 F isotope, which has a spin of 1/2 and has the highest receptivity of heteronuclei at 83% that of 1 H. Nonetheless, this high receptivity is not sufficient to garner the necessary sensitivity for many applications. Thus, in vivo translation of 19 F MRI remains challenging, though successful imaging of small animals has been achieved with highly fluorinated nanoparticles or liposomes, ,, perfluoropolyethers, , and small organic molecules. , Following the success of ParaCEST (paramagnetic chemical exchange saturation transfer) agents, we and others ,− have attempted to use the same approach to increase the sensitivity of fluorinated probes on a per 19 F basis by decreasing their longitudinal relaxation times ( T 1 ) via the incorporation of paramagnetic metals. Decreasing the T 1 of 19 F enables the acquisition of more scans per given amount of time, a critical restriction for in vivo imaging, which is time-constrained.…”

Section: Introductionmentioning

confidence: 99%

Exploiting the Fluxionality of Lanthanide Complexes in the Design of Paramagnetic Fluorine Probes

et al. 2022

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Fluorine-19 MRI is increasingly being considered as a tool for biomolecular imaging, but the very poor sensitivity of this technique has limited most applications. Previous studies have long established that increasing the sensitivity of 19F molecular probes requires increasing the number of fluorine nuclei per probe as well as decreasing their longitudinal relaxation time. The latter is easily achieved by positioning the fluorine atoms in close proximity to a paramagnetic metal ion such as a lanthanide(III). Increasing the number of fluorine atoms per molecule, however, is only useful inasmuch as all of the fluorine nuclei are chemically equivalent. Previous attempts to achieve this equivalency have focused on designing highly symmetric and rigid fluorinated macrocyclic ligands. A much simpler approach consists of exploiting highly fluxional lanthanide complexes with open coordination sites that have a high affinity for phosphated and phosphonated species. Computational studies indicate that LnIII-TREN-MAM is highly fluxional, rapidly interconverting between at least six distinct isomers. In neutral water at room temperature, LnIII-TREN-MAM binds two or three equivalents of fluorinated phosphonates. The close proximity of the 19F nuclei to the LnIII center in the ternary complex decreases the relaxation times of the fluorine nuclei up to 40-fold. Advantageously, the fluorophosphonate-bound lanthanide complex is also highly fluxional such that all 19F nuclei are chemically equivalent and display a single 19F signal with a small LIS. Dynamic averaging of fluxional fluorinated supramolecular assemblies thus produces effective 19F MR systems.

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Section: Introductionmentioning

confidence: 99%

Exploiting the Fluxionality of Lanthanide Complexes in the Design of Paramagnetic Fluorine Probes

et al. 2022

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“…This would allow the computation of quantitative concentration maps with the help of an external standard. Retrospective techniques based on the steady-state signal equation can be employed for the UTE sequence employed in this study [117], while more complex, model-based approaches would be recommended if a RARE sequence were employed [118]. Finally, should sensitive hardware that enables alternating or even simultaneous 1 H and 19 F acquisition be available, motion correction techniques could be employed to reduce the need for restraining the subject under investigation and promote the successful outcome of the experiment without compromising animal welfare or patient comfort [119,120].…”

Section: Discussionmentioning

confidence: 99%

First in vivo fluorine-19 magnetic resonance imaging of the multiple sclerosis drug siponimod

Starke¹,

Millward²,

Prinz³

et al. 2023

Theranostics

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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 (S1P) 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.

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Quantifying model uncertainty for semantic segmentation of Fluorine-19 MRI using stochastic gradient MCMC

Javanbakhat,

Starke,

Waiczies

et al. 2024

Computer Vision and Image Understanding

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B₁inhomogeneity correction of RARE MRI at low SNR: Quantitative in vivo¹⁹F MRI of mouse neuroinflammation with a cryogenically‐cooled transceive surface radiofrequency probe

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 5 publications

References 54 publications

Exploiting the Fluxionality of Lanthanide Complexes in the Design of Paramagnetic Fluorine Probes

Exploiting the Fluxionality of Lanthanide Complexes in the Design of Paramagnetic Fluorine Probes

First in vivo fluorine-19 magnetic resonance imaging of the multiple sclerosis drug siponimod

Quantifying model uncertainty for semantic segmentation of Fluorine-19 MRI using stochastic gradient MCMC

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B1inhomogeneity correction of RARE MRI at low SNR: Quantitative in vivo19F MRI of mouse neuroinflammation with a cryogenically‐cooled transceive surface radiofrequency probe

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 5 publications

References 54 publications

Exploiting the Fluxionality of Lanthanide Complexes in the Design of Paramagnetic Fluorine Probes

Exploiting the Fluxionality of Lanthanide Complexes in the Design of Paramagnetic Fluorine Probes

First in vivo fluorine-19 magnetic resonance imaging of the multiple sclerosis drug siponimod

Quantifying model uncertainty for semantic segmentation of Fluorine-19 MRI using stochastic gradient MCMC

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B₁inhomogeneity correction of RARE MRI at low SNR: Quantitative in vivo¹⁹F MRI of mouse neuroinflammation with a cryogenically‐cooled transceive surface radiofrequency probe