Synthesis, radiosynthesis and biochemical evaluation of fluorinated analogues of sphingosine-1-phosphate receptor 3 specific antagonists using PET.

[Display omitted] • New fluorinated sphingosine-1-phosphate receptor 3 (S1P 3) antagonists have been synthesized. • The most active one was 18F-labelled for application in Positron Emission Tomography (PET) • This compound has good serum stability and medium lipophilicity. • In vivo biodistribution based on PET imaging study in mice showed high uptake in the myocardium. Sphingosine-1-phosphate and its receptors (S1PRs) are involved in several diseases such as auto immunity, inflammation and cardiovascular disorders. The S1P analogue fingolimod (Gilenya®) is currently in use for the treatment of relapsing multiple sclerosis. S1PRs are also promising targets for clinical molecular imaging in vivo. The organ distribution of individual S1PRs can be potentially achieved by using S1PR subtype-specific (radiolabeled) chemical probes. Here, we report our efforts on synthesis and in vivo potency determination of new ligands for the S1P receptor 3 (S1P 3) based on the S1P 3 antagonist TY-52156 and in validation of a potential imaging tracer in vivo using Positron Emission Tomography (PET) after 18F-labelling. A p -fluorophenyl derivative exhibited excellent S1P 3 antagonist activity in vitro , good serum stability, and medium lipophilicity. In vivo biodistribution experiments using 18F-PET exhibited significant uptake in the myocardium suggesting potential applications in cardiac imaging. [ABSTRACT FROM AUTHOR]