Assessment of a 6-arylaminobenzamide lead derivative as a potential core scaffold for S1P5 positron emission tomography radiotracer development

Robert C Shaw; Timaeus E F Morgan; Holly McErlain; Carlos J Alcaide-Corral; Adam D Waldman; Dmitry Soloviev; David Y Lewis; Andrew Sutherland; Adriana A S Tavares

doi:10.1016/j.bmc.2024.118057

Assessment of a 6-arylaminobenzamide lead derivative as a potential core scaffold for S1P₅ positron emission tomography radiotracer development

Bioorg Med Chem. 2025 Jan 3:119:118057. doi: 10.1016/j.bmc.2024.118057. Online ahead of print.

Authors

Robert C Shaw¹, Timaeus E F Morgan², Holly McErlain², Carlos J Alcaide-Corral¹, Adam D Waldman³, Dmitry Soloviev⁴, David Y Lewis⁵, Andrew Sutherland², Adriana A S Tavares⁶

Affiliations

¹ University/BHF Centre for Cardiovascular Sciences, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ UK; Edinburgh Imaging, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ UK.
² School of Chemistry, University of Glasgow, University Avenue, Glasgow G12 8QQ UK.
³ Centre for Clinical Brain Sciences, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB UK.
⁴ School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1QH UK.
⁵ School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1QH UK; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD UK.
⁶ University/BHF Centre for Cardiovascular Sciences, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ UK; Edinburgh Imaging, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ UK. Electronic address: adriana.tavares@ed.ac.uk.

PMID: 39798239
DOI: 10.1016/j.bmc.2024.118057

Abstract

Sphingosine-1-phosphate-5 receptors (S1P₅) are predominantly expressed in oligodendrocytes and as a result have been proposed as an important target in Multiple Sclerosis (MS). Selective S1P₅ radiotracers could enable in vivo positron emission tomography (PET) imaging of oligodendrocytes activity. Here we report the synthesis, radiolabelling and first preclinical evaluation of the pharmacokinetics and binding properties of a lead 6-arylaminobenzamide derivative, 6-(mesitylamino)-2-methoxy-3-methylbenzamide (also named as TEFM180), as a potential core scaffold for development of novel S1P₅ PET radiotracers. Following intravenous bolus injection, TEFM180 was found to quickly enter the brain with good brain:blood ratios and subsequent rapid clearance. Autoradiography studies showed that [³H]TEFM180 had a high affinity for its target (K_D = 2.8 nM), with moderate levels of non-displaceable binding. Distribution of [³H]TEFM180 in the brain was found to be consistent with S1P₅ expression and showed a binding potential (BP) of >2-3 in white matter rich regions. Overall, TEFM180 offers a good initial platform for development of future radiotracers targeting S1P₅.

Keywords: Aminobenzamides; Positron emission tomography; Radiotracer; Radiotracer development; S1P(5); Sphingosine-1-phosphate-5 receptors.