Discovery of a Promising Fluorine-18 Positron Emission Tomography Radiotracer for Imaging Sphingosine-1-Phosphate Receptor 1 in the Brain

Sphingosine-1-phosphate receptor 1 (S1PR1) is recognized as a novel therapeutic and diagnostic target in neurological disorders. We recently transferred the S1PR1 radioligand [¹¹C]CS1P1 into clinical investigation for multiple sclerosis. Herein, we reported the design, synthesis and evaluation of novel F-18 S1PR1 radioligands. We combined the structural advantages of our two lead S1PR1 radioligands and synthesized 14 new S1PR1 compounds, then performed F-18 radiochemistry on the most promising compounds. Compound 6h is potent (IC₅₀ = 8.7 nM) and selective for S1PR1. [¹⁸F]6h exhibited a high uptake in macaque brain (SUV > 3.0) and favorable brain washout pharmacokinetics in positron emission tomography (PET) study. PET blocking and displacement studies confirmed the specificity of [¹⁸F]6h in vivo. Radiometabolite analysis confirmed no radiometabolite of [¹⁸F]6h entered into the brain to confound the PET measurement. In summary, [¹⁸F]6h is a promising radioligand to image S1PR1 and worth translational clinical investigation for humans with brain disorders.