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

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.