Chapter 11 Fluorinated Natural Compounds and Synthetic Drugs

Niendorf, Thoralf; Ji, Yiyi; Waiczies, Sonia

doi:10.1201/9781315364605-12

Cited by 3 publications

(3 citation statements)

References 104 publications

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“…More than one-third of prescribed drugs contain fluorine ( 19 F), which generally improves their pharmacokinetic properties. − Fluorination also opens an opportunity to noninvasively study drugs in vivo using 19 F magnetic resonance imaging (MRI). This prospect heralds an age when exact locations and concentrations of drugs can be determined in patients to inform drug therapies. − The signal-to-noise ratio (SNR) achieved with 19 F MRI is limited because of the low availability of 19 F nuclei in vivo. Additionally, specific 19 F magnetic resonance (MR) properties (chemical shift, spectral shape, e.g., full width at half maximum or FWHM, spin–lattice ( T 1 ) and spin–spin ( T 2 ) relaxation times) and pharmacological properties (metabolism, protein binding, etc.)…”

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Pentafluorosulfanyl (SF₅) as a Superior ¹⁹F Magnetic Resonance Reporter Group: Signal Detection and Biological Activity of Teriflunomide Derivatives

et al. 2021

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Fluorine ( 19 F) magnetic resonance imaging (MRI) is severely limited by a low signal-to noise ratio (SNR), and tapping it for 19 F drug detection in vivo still poses a significant challenge. However, it bears the potential for label-free theranostic imaging. Recently, we detected the fluorinated dihydroorotate dehydrogenase (DHODH) inhibitor teriflunomide (TF) noninvasively in an animal model of multiple sclerosis (MS) using 19 F MR spectroscopy (MRS). In the present study, we probed distinct modifications to the CF 3 group of TF to improve its SNR. This revealed SF 5 as a superior alternative to the CF 3 group. The value of the SF 5 bioisostere as a 19 F MRI reporter group within a biological or pharmacological context is by far underexplored. Here, we compared the biological and pharmacological activities of different TF derivatives and their 19 F MR properties (chemical shift and relaxation times). The 19 F MR SNR efficiency of three MRI methods revealed that SF 5 -substituted TF has the highest 19 F MR SNR efficiency in combination with an ultrashort echo-time (UTE) MRI method. Chemical modifications did not reduce pharmacological or biological activity as shown in the in vitro dihydroorotate dehydrogenase enzyme and T cell proliferation assays. Instead, SF 5 -substituted TF showed an improved capacity to inhibit T cell proliferation, indicating better anti-inflammatory activity and its suitability as a viable bioisostere in this context. This study proposes SF 5 as a novel superior 19 F MR reporter group for the MS drug teriflunomide.

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Pentafluorosulfanyl (SF₅) as a Superior ¹⁹F Magnetic Resonance Reporter Group: Signal Detection and Biological Activity of Teriflunomide Derivatives

et al. 2021

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“…Pharmacokinetic imaging is commonly conducted using autoradiography and single-photon emission computed tomography (SPECT) [21], which involve radioactive labelling methods that are unsuitable for routine clinical practice. 19 F MRI is an additional tool for pharmacokinetic imaging that does not involve harmful ionizing radiation, making this approach particularly appealing [22,23]. A non-invasive method for localizing and quantifying fluorinated drugs such as siponimod in relevant organs during disease could allow for the integration of imaging and therapy, to establish a theranostic strategy that can tailor treatment to individual patient responses and pharmacokinetics [24,25].…”

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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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Toward 19F magnetic resonance thermometry: spin–lattice and spin–spin-relaxation times and temperature dependence of fluorinated drugs at 9.4 T

Prinz

Delgado

Eigentler

et al. 2018

Magn Reson Mater Phy

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Chapter 11 Fluorinated Natural Compounds and Synthetic Drugs

Cited by 3 publications

References 104 publications

Pentafluorosulfanyl (SF₅) as a Superior ¹⁹F Magnetic Resonance Reporter Group: Signal Detection and Biological Activity of Teriflunomide Derivatives

Pentafluorosulfanyl (SF₅) as a Superior ¹⁹F Magnetic Resonance Reporter Group: Signal Detection and Biological Activity of Teriflunomide Derivatives

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

Toward 19F magnetic resonance thermometry: spin–lattice and spin–spin-relaxation times and temperature dependence of fluorinated drugs at 9.4 T

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Chapter 11 Fluorinated Natural Compounds and Synthetic Drugs

Cited by 3 publications

References 104 publications

Pentafluorosulfanyl (SF5) as a Superior 19F Magnetic Resonance Reporter Group: Signal Detection and Biological Activity of Teriflunomide Derivatives

Pentafluorosulfanyl (SF5) as a Superior 19F Magnetic Resonance Reporter Group: Signal Detection and Biological Activity of Teriflunomide Derivatives

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

Toward 19F magnetic resonance thermometry: spin–lattice and spin–spin-relaxation times and temperature dependence of fluorinated drugs at 9.4 T

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Pentafluorosulfanyl (SF₅) as a Superior ¹⁹F Magnetic Resonance Reporter Group: Signal Detection and Biological Activity of Teriflunomide Derivatives

Pentafluorosulfanyl (SF₅) as a Superior ¹⁹F Magnetic Resonance Reporter Group: Signal Detection and Biological Activity of Teriflunomide Derivatives