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

Abstract

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.

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:
Research Org.:
Washington Univ., St. Louis, MO (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1466768
Grant/Contract Number:  
SC0008432; SC0012737
Resource 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)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 62 RADIOLOGY AND NUCLEAR MEDICINE

Citation Formats

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., 2016. 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. Thu . "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}
}

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