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.