Synthesis of new ligands for targeting the S1P1 receptor. Issue 5 (1st March 2015) - Schilson, Stefanie S.
Graphical abstract: A series of fluorinated sphingosine derivatives including aliphatic FTY720 analogues have been tested as S1P1 receptor agonists. Bioisosteric replacement of the 3-OH group by fluorine or attachment of this substituent in the proximity of the crucial 2-amino-1, 3-diol moiety resulted in drop of potency, while ω-fluorinated analogues were equally potent as their parent hydrocarbons. 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.