Design, Synthesis, and In Vitro and In Vivo Evaluation of an (18)F-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 (18)F-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 [(18)F]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 [(18)F]28c is a S1P1 PET tracer with high potential for imaging S1P1 in vivo.
Department of Radiology, Washington University School of Medicine , 510 South Kingshighway Boulevard, St. Louis, Missouri 63110, United States.
Adam J
AJ
Rosenberg
Department of Radiology, Washington University School of Medicine , 510 South Kingshighway Boulevard, St. Louis, Missouri 63110, United States.
Hui
H
Liu
Department of Radiology, Washington University School of Medicine , 510 South Kingshighway Boulevard, St. Louis, Missouri 63110, United States.
Hongjun
H
Jin
Department of Radiology, Washington University School of Medicine , 510 South Kingshighway Boulevard, St. Louis, Missouri 63110, United States.
Xuyi
X
Yue
The Scripps Research Institute Molecular Screening Center , 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
Sean
S
Riley
The Scripps Research Institute Molecular Screening Center , 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
Steven J
SJ
Brown
Department of Radiology, Washington University School of Medicine , 510 South Kingshighway Boulevard, St. Louis, Missouri 63110, United States.
Zhude
Z
Tu
D000818:Animals; D005462:Fluorine Radioisotopes / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000032:analysis* / Q000378:metabolism
D005462:Fluorine Radioisotopes; D008024:Ligands; D049349:Receptors, Lysosphingolipid