Pentafluorosulfanyl (SF(5)) as a superior (19)F magnetic resonance reporter group: signal detection and biological activity of teriflunomide derivatives
Authors
- C. Prinz
- L. Starke
- T.F. Ramspoth
- J. Kerkering
- V. Martos Riaño
- J. Paul
- M. Neuenschwander
- A. Oder
- S. Radetzki
- S. Adelhoefer
- P. Ramos Delgado
- M. Aravina
- J.M. Millward
- A. Fillmer
- F. Paul
- V. Siffrin
- J.P. von Kries
- T. Niendorf
- M. Nazaré
- S. Waiczies
Journal
- ACS Sensors
Citation
- ACS Sens 6 (11): 3948–3956
Abstract
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.