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Title: Design, Synthesis, and In Vitro and In Vivo Evaluation of an 18 F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P 1) PET Tracer

We present that sphingosine 1-phosphate receptor 1 (S1P 1) plays a pivotal signaling role in inflammatory response; because S1P 1 modulation has been identified as a therapeutic target for various diseases, a PET tracer for S1P 1 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 S1P 1 (S1P 1 IC 50 < 10 nM, >100-fold selectivity for S1P 1 over S1P 2 and S1P 3). The most potent ligand, 28c (IC 50 = 2.63 nM for S1P 1) was 18F-labeled and evaluated in a mouse model of LPS-induced acute liver injury to determine its S1P 1-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 S1P 1 in the LPS model was confirmed by immunohistochemical analysis (IHC). Finally, these data suggest that [ 18F]28c is a S1P 1 PET tracer with high potential for imaging S1P 1 in vivo.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [2] ;  [1]
  1. Washington University School of Medicine, St. Louis, MO (United States). Department of Radiology
  2. The Scripps Research Institute Molecular Screening Center, La Jolla, CA (United States)
Publication Date:
Grant/Contract Number:
SC0008432; SC0012737
Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 59; Journal Issue: 13; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Research Org:
Washington Univ., St. Louis, MO (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 62 RADIOLOGY AND NUCLEAR MEDICINE
OSTI Identifier:
1466768

Rosenberg, Adam J., Liu, Hui, Jin, Hongjun, Yue, Xuyi, Riley, Sean, Brown, Steven J., and Tu, Zhude. Design, Synthesis, and In Vitro and In Vivo Evaluation of an 18 F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P1) PET Tracer. United States: N. p., Web. doi:10.1021/acs.jmedchem.6b00390.
Rosenberg, Adam J., Liu, Hui, Jin, Hongjun, Yue, Xuyi, Riley, Sean, Brown, Steven J., & Tu, Zhude. Design, Synthesis, and In Vitro and In Vivo Evaluation of an 18 F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P1) PET Tracer. United States. doi:10.1021/acs.jmedchem.6b00390.
Rosenberg, Adam J., Liu, Hui, Jin, Hongjun, Yue, Xuyi, Riley, Sean, Brown, Steven J., and Tu, Zhude. 2016. "Design, Synthesis, and In Vitro and In Vivo Evaluation of an 18 F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P1) PET Tracer". United States. doi:10.1021/acs.jmedchem.6b00390. https://www.osti.gov/servlets/purl/1466768.
@article{osti_1466768,
title = {Design, Synthesis, and In Vitro and In Vivo Evaluation of an 18 F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P1) PET Tracer},
author = {Rosenberg, Adam J. and Liu, Hui and Jin, Hongjun and Yue, Xuyi and Riley, Sean and Brown, Steven J. and Tu, Zhude},
abstractNote = {We present that 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). Finally, these data suggest that [18F]28c is a S1P1 PET tracer with high potential for imaging S1P1 in vivo.},
doi = {10.1021/acs.jmedchem.6b00390},
journal = {Journal of Medicinal Chemistry},
number = 13,
volume = 59,
place = {United States},
year = {2016},
month = {6}
}