Design, Synthesis, and in Vitro and in Vivo Evaluation of an ¹⁸F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P₁) PET Tracer

Sphingosine 1-phosphate receptor 1 (S1P₁) plays a pivotal signaling role in inflammatory response; because S1P₁ modulation has been identified as a therapeutic target for various diseases, a PET tracer for S1P₁ would be a useful tool. Fourteen fluorine-containing analogues of S1P ligands were synthesized and their in vitro binding potency measured; four had high potency and selectivity for S1P₁ (S1P₁ IC₅₀ < 10 nM, >100-fold selectivity for S1P₁ over S1P₂ and S1P₃). The most potent ligand, 28c (IC₅₀ = 2.63 nM for S1P₁) was ¹⁸F-labeled and evaluated in a mouse model of LPS-induced acute liver injury to determine its S1P₁-binding specificity. The results from biodistribution, autoradiography, and microPET imaging showed higher [¹⁸F]28c accumulation in the liver of LPS-treated mice than controls. Increased expression of S1P₁ in the LPS model was confirmed by immunohistochemical analysis (IHC). These data suggest that [¹⁸F]28c is a S1P₁ PET tracer with high potential for imaging S1P₁ in vivo.