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

Volker Siffrin,Siegfried Adelhoefer,Jens-Peter Von Kries,Andreas Oder,Ariane Fillmer,Paula Ramos Delgado,Sonia Waiczies,Christian Prinz,Tizian-Frank Ramspoth,Marc Nazaré,Janis Kerkering,Mariya Aravina,Thoralf Niendorf,Friedemann Paul,Ludger Starke,Martin Neuenschwander,Jérôme Paul,Silke Radetzki,Vera Martos Riaño,Jason M Millward

doi:10.1021/acssensors.1c01024

Abstract

Fluorine (19F) magnetic resonance imaging (MRI) is severely limited by a low signal-to noise ratio (SNR), and tapping it for 19F 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 19F MR spectroscopy (MRS). In the present study, we probed distinct modifications to the CF3 group of TF to improve its SNR. This revealed SF5 as a superior alternative to the CF3 group. The value of the SF5 bioisostere as a 19F 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 19F MR properties (chemical shift and relaxation times). The 19F MR SNR efficiency of three MRI methods revealed that SF5-substituted TF has the highest 19F 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, SF5-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 SF5 as a novel superior 19F MR reporter group for the MS drug teriflunomide.

Highlights

Is severely limited by a low signal-to noise ratio (SNR), and tapping it for 19F drug detection in vivo still poses a significant challenge
The 19F magnetic resonance (MR) SNR efficiency of three magnetic resonance imaging (MRI) methods revealed that SF5-substituted TF has the highest 19F MR SNR efficiency in combination with an ultrashort echo-time (UTE) MRI method
The trifluoromethoxy-substituted TF (CF3O-TF) and pentafluorosulfanyl-substituted TF (SF5-TF) demonstrated equal or even better pharmacological and antiproliferative activities compared to TF (CF3-TF) as shown by the IC50 values for dihydroorotate dehydrogenase (DHODH) inhibition in in vitro enzyme and proliferation assays (Table 1)

Summary

Introduction

Is severely limited by a low signal-to noise ratio (SNR), and tapping it for 19F drug detection in vivo still poses a significant challenge. More than one-third of prescribed drugs contain fluorine (19F), which generally improves their pharmacokinetic properties.[1−5] Fluorination opens an opportunity to noninvasively study drugs in vivo using 19F 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.[2−8] The signal-to-noise ratio (SNR) achieved with 19F MRI is limited because of the low availability of 19F nuclei in vivo. The application of 19F MRI continues to expand, e.g., to track immunotherapies,[9] investigate temperature-dependent molecular switches,[10] image tumors using pH-responsive probes,[11] or monitor inflammatory processes in vivo.[12,13] The implications of

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Results

Conclusion