Synthesis of new ligands for targeting the S1P1 receptor

Stefanie S Schilson; Petra Keul; Rizwan S Shaikh; Michael Schäfers; Bodo Levkau; Günter Haufe

doi:10.1016/j.bmc.2015.01.014

Synthesis of new ligands for targeting the S1P1 receptor

Bioorg Med Chem. 2015 Mar 1;23(5):1011-26. doi: 10.1016/j.bmc.2015.01.014. Epub 2015 Jan 16.

Authors

Stefanie S Schilson¹, Petra Keul², Rizwan S Shaikh³, Michael Schäfers⁴, Bodo Levkau², Günter Haufe⁵

Affiliations

¹ Organic Chemistry Institute, University of Münster, Corrensstraße 40, D-48149 Münster, Germany.
² Institute for Pathophysiology, Westdeutsches Herz- und Gefäßzentrum, University Hospital, Essen, University of Duisburg-Essen, Hufelandstraße 55, D-45122 Essen, Germany.
³ Organic Chemistry Institute, University of Münster, Corrensstraße 40, D-48149 Münster, Germany; NRW Graduate School of Chemistry, University of Münster, Wilhelm-Klemm-Straße 10, D-48149 Münster, Germany.
⁴ Department of Nuclear Medicine, University of Münster, Albert-Schweizer-Campus 1, D-48149 Münster, Germany; European Institute for Molecular Imaging, University of Münster, Waldeyerstraße 15, D-48149 Münster, Germany; Cells-in-Motion, Centre of Excellence, University of Münster, Waldeyerstraße 15, D-48149 Münster, Germany.
⁵ Organic Chemistry Institute, University of Münster, Corrensstraße 40, D-48149 Münster, Germany; European Institute for Molecular Imaging, University of Münster, Waldeyerstraße 15, D-48149 Münster, Germany; Cells-in-Motion, Centre of Excellence, University of Münster, Waldeyerstraße 15, D-48149 Münster, Germany. Electronic address: haufe@uni-muenster.de.

PMID: 25656338
DOI: 10.1016/j.bmc.2015.01.014

Abstract

Sphingosine-1-phosphate (S1P) influences various fundamental biological processes by interacting with a family of five G protein-coupled receptors (S1P1-5). FTY720, a sphingosine analogue, which was approved for treatment of relapsing forms of multiple sclerosis, is phosphorylated in vivo and acts as an agonist of four of the five S1P receptor subtypes. Starting from these lead structures we developed new agonists for the S1P1 receptor. The biological activity was tested in vivo and promising ligands were fluorinated at different positions to identify candidates for positron emission tomography (PET) imaging after [(18)F]-labelling. The radioligands shall enable the imaging of S1P1 receptor expression in vivo and thus may serve as novel imaging markers of S1P-related diseases.

Keywords: FTY720 analogues; Fluorine; G protein-coupled receptors; S1P(1) receptor agonists; Sphingosine-1-phosphate (S1P); Structure–activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CHO Cells
Cricetinae
Cricetulus
Fingolimod Hydrochloride / chemical synthesis*
Fingolimod Hydrochloride / chemistry
Fingolimod Hydrochloride / pharmacology*
Humans
Immunosuppressive Agents / chemical synthesis
Immunosuppressive Agents / chemistry
Immunosuppressive Agents / pharmacology
Ligands
Mice
Receptors, Lysosphingolipid / drug effects*
Receptors, Lysosphingolipid / metabolism

Substances

Immunosuppressive Agents
Ligands
Receptors, Lysosphingolipid
Fingolimod Hydrochloride