Synthesis and evaluation of 6-arylaminobenzamides as positron emission tomography imaging ligands for the sphingosine-1-phosphate-5 receptor.

The sphingosine-1-phosphate-5 (S1P) receptor is one of the five membrane G protein-coupled receptors that are activated by the lysophospholipid, sphingosine-1-phosphate, resulting in regulation of many cellular processes. S1P receptors are located on oligodendrocytes and are proposed to influence oligodendrocyte physiology. Understanding S1P modulation during processes such as remyelination could have potential applications for demyelinating CNS disorders such as multiple sclerosis (MS). Herein, we report the synthesis and preliminary evaluation of a series of fluorinated 6-arylaminobenzamides as positron emission tomography (PET) ligands of S1P. Pharmacokinetic screening and binding evaluation using a [S]GTPγS assay led to the discovery of TEFM78, a selective and high affinity agonist of S1P. Radiosynthesis of [F]TEFM78 allowed pilot PET imaging studies in an animal model, which showed that [F]TEFM78 can cross the blood brain barrier with good uptake in rat brain and spinal cord.