TY - JOUR
T1 - Design, Synthesis, and in Vitro and in Vivo Evaluation of an 18F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P1) PET Tracer
AU - Rosenberg, Adam J.
AU - Liu, Hui
AU - Jin, Hongjun
AU - Yue, Xuyi
AU - Riley, Sean
AU - Brown, Steven J.
AU - Tu, Zhude
N1 - Funding Information:
We thank Ms. Lynne Jones for many helpful discussions. This research work was directly supported by the Department of Energy (DOE, No. DESC0008432 and No. DESC0012737), and the National Institutes of Health through the National Institute of Neurological Disorders and Stroke (NINDS, R01NS075527), and the National Institute of Mental Health (NIMH, No. MH092797).
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/7/14
Y1 - 2016/7/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84978696460&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.6b00390
DO - 10.1021/acs.jmedchem.6b00390
M3 - Article
C2 - 27280499
AN - SCOPUS:84978696460
SN - 0022-2623
VL - 59
SP - 6201
EP - 6220
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 13
ER -