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.