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

Abstract

The sphingosine-1-phosphate-5 (S1P₅) 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. S1P₅ receptors are located on oligodendrocytes and are proposed to influence oligodendrocyte physiology. Understanding S1P₅ 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 S1P₅. Pharmacokinetic screening and binding evaluation using a [³⁵S]GTPγS assay led to the discovery of TEFM78, a selective and high affinity agonist of S1P₅. Radiosynthesis of [¹⁸F]TEFM78 allowed pilot PET imaging studies in an animal model, which showed that [¹⁸F]TEFM78 can cross the blood brain barrier with good uptake in rat brain and spinal cord.