Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates

Luo, Zonghua; Han, Junbin; Liu, Hui; Rosenberg, Adam J.; Chen, Delphine L.; Gropler, Robert J.; Perlmutter, Joel S.; Tu, Zhude

doi:10.1039/c8ob02609b

Title: Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates

Abstract

A series of seventeen hydroxyl-containing sphingosine 1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized. Their in vitro binding potencies were determined using [³²P]S1P competitive binding assays. Compounds 10a, 17a, 17b, and 24 exhibited high S1PR1 binding potencies with IC₅₀ values ranging from 3.9 to 15.4 nM and also displayed high selectivity for S1PR1 over other S1P receptor subtypes (IC₅₀ > 1000 nM for S1PR2–5). The most potent compounds 10a, 17a, 17b, and 24 were subsequently radiolabeled with F-18 in high yields and purities. MicroPET studies in cynomolgus macaque showed that [¹⁸F]10a, [¹⁸F]17a, and [¹⁸F]17b but not [18F]24 crossed the blood brain barrier and had high initial brain uptake. Further validation of [¹⁸F]10a, [¹⁸F]17a, and [¹⁸F]17b in preclinical models of neuroinflammation is warranted to identify a suitable PET radioligand to quantify S1PR1 expression in vivo as a metric of an inflammatory response.

Authors:

^[1]; Han, Junbin ^[1];

^[1];

^[1]; Chen, Delphine L. ^[1]; Gropler, Robert J. ^[1];

^[1];

^[1]

Washington Univ., St. Louis, MO (United States)

Publication Date:: Thu Nov 15 00:00:00 EST 2018

Research Org.:: Washington Univ., St. Louis, MO (United States)

Sponsoring Org.:: USDOE Office of Science (SC)

OSTI Identifier:: 1611052

Alternate Identifier(s):: OSTI ID: 1483021

Grant/Contract Number:: SC0008432

Resource Type:: Accepted Manuscript

Journal Name:: Organic and Biomolecular Chemistry

Additional Journal Information:: Journal Volume: 16; Journal Issue: 47; Journal ID: ISSN 1477-0520

Publisher:: Royal Society of Chemistry

Country of Publication:: United States

Language:: English

Subject:: 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Chemistry

Citation Formats


                    Luo, Zonghua, Han, Junbin, Liu, Hui, Rosenberg, Adam J., Chen, Delphine L., Gropler, Robert J., Perlmutter, Joel S., and Tu, Zhude. Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates.  United States: N. p., 2018. 
Web.  doi:10.1039/c8ob02609b.

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                    Luo, Zonghua, Han, Junbin, Liu, Hui, Rosenberg, Adam J., Chen, Delphine L., Gropler, Robert J., Perlmutter, Joel S., & Tu, Zhude. Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates.  United States.  https://doi.org/10.1039/c8ob02609b

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                    Luo, Zonghua, Han, Junbin, Liu, Hui, Rosenberg, Adam J., Chen, Delphine L., Gropler, Robert J., Perlmutter, Joel S., and Tu, Zhude. Thu .  
"Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates".  United States.  https://doi.org/10.1039/c8ob02609b.  https://www.osti.gov/servlets/purl/1611052.

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@article{osti_1611052,

  title        = {Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates},

  author       = {Luo, Zonghua and Han, Junbin and Liu, Hui and Rosenberg, Adam J. and Chen, Delphine L. and Gropler, Robert J. and Perlmutter, Joel S. and Tu, Zhude},

  abstractNote = {A series of seventeen hydroxyl-containing sphingosine 1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized. Their in vitro binding potencies were determined using [32P]S1P competitive binding assays. Compounds 10a, 17a, 17b, and 24 exhibited high S1PR1 binding potencies with IC50 values ranging from 3.9 to 15.4 nM and also displayed high selectivity for S1PR1 over other S1P receptor subtypes (IC50 > 1000 nM for S1PR2–5). The most potent compounds 10a, 17a, 17b, and 24 were subsequently radiolabeled with F-18 in high yields and purities. MicroPET studies in cynomolgus macaque showed that [18F]10a, [18F]17a, and [18F]17b but not [18F]24 crossed the blood brain barrier and had high initial brain uptake. Further validation of [18F]10a, [18F]17a, and [18F]17b in preclinical models of neuroinflammation is warranted to identify a suitable PET radioligand to quantify S1PR1 expression in vivo as a metric of an inflammatory response.},

  doi          = {10.1039/c8ob02609b},

  journal      = {Organic and Biomolecular Chemistry},

  number       = 47,

  volume       = 16,

  place        = {United States},

  year         = {Thu Nov 15 00:00:00 EST 2018},

  month        = {Thu Nov 15 00:00:00 EST 2018}

}

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Molecular imaging of multiple sclerosis: from the clinical demand to novel radiotracers
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Title: Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates

Abstract

Citation Formats

Defining the clinical course of multiple sclerosis: Results of an international survey journal, April 1996

PET radiotracers: crossing the blood–brain barrier and surviving metabolism journal, August 2009

S1P1 receptor subtype inhibits demyelination and regulates chemokine release in cerebellar slice cultures journal, November 2011

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Relevance and potential of sphingosine-1-phosphate in vascular inflammatory disease journal, November 2008

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Current drug research on PEGylation with small molecular agents journal, March 2013

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An update on the biology of sphingosine 1-phosphate receptors journal, January 2014

A practical process for the preparation of [32P]S1P and binding assay for S1P receptor ligands journal, August 2015

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A promising carbon-11-labeled sphingosine-1-phosphate receptor 1-specific PET tracer for imaging vascular injury journal, February 2016

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Molecular cloning of a novel putative G protein-coupled receptor from rat aortic smooth muscle. Downregulation of the mRNA level by the cyclic AMP messenger pathway journal, June 1994

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Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues journal, October 2014

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Molecular Cloning and Functional Characterization of Murine Sphingosine Kinase journal, September 1998

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy journal, April 2015

Sphingolipid metabolites in inflammatory disease journal, June 2014

Synthesis of fluorinated analogues of sphingosine-1-phosphate antagonists as potential radiotracers for molecular imaging using positron emission tomography journal, October 2014

Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy journal, June 2008

Sphingosine-1-phosphate receptor-1 (S1P1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease journal, April 2016

Imaging S1P1 activation in vivo journal, May 2015

Syntheses and in vitro evaluation of new S1PR1 compounds and initial evaluation of a lead F-18 radiotracer in rodents journal, April 2018

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Sphingosine-1-Phosphate as a Ligand for the G Protein-Coupled Receptor EDG-1 journal, March 1998

Discovery and Structure–Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P 1 ) journal, July 2016

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STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors journal, November 2010

Pegylation Improves the Pharmacokinetics and Bioavailability of Small-Molecule Drugs Hydrolyzable by Esterases: A Study of Phospho-Ibuprofen journal, July 2014

Redox Behavior of Ferrocene-Containing Rotaxane: Transposition of the Rotaxane Wheel by Redox Reaction of a Ferrocene Moiety Tethered at the End of the Axle journal, May 2004

An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors. journal, June 1990

Molecular imaging of multiple sclerosis: from the clinical demand to novel radiotracers journal, April 2019

Molecular imaging of multiple sclerosis: from the clinical demand to novel radiotracers journal, April 2019

Defining the clinical course of multiple sclerosis: Results of an international survey
journal, April 1996

PET radiotracers: crossing the blood–brain barrier and surviving metabolism
journal, August 2009

S1P1 receptor subtype inhibits demyelination and regulates chemokine release in cerebellar slice cultures
journal, November 2011

¹⁸ F Stilbenes and Styrylpyridines for PET Imaging of Aβ Plaques in Alzheimer’s Disease: A Miniperspective
journal, February 2010

Relevance and potential of sphingosine-1-phosphate in vascular inflammatory disease
journal, November 2008

Sphingosine-1-Phosphate Links Persistent STAT3 Activation, Chronic Intestinal Inflammation, and Development of Colitis-Associated Cancer
journal, January 2013

Multidentate ¹⁸ F-Polypegylated Styrylpyridines As Imaging Agents for Aβ Plaques in Cerebral Amyloid Angiopathy (CAA)
journal, December 2011

Effect of pegylation on pharmaceuticals
journal, March 2003

PET Study of Sphingosine-1-Phosphate Receptor 1 Expression in Response to Vascular Inflammation in a Rat Model of Carotid Injury
journal, January 2017

Current drug research on PEGylation with small molecular agents
journal, March 2013

Fingolimod modulates microglial activation to augment markers of remyelination
journal, January 2011

FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation
journal, December 2010

Impact of Fingolimod Therapy on Magnetic Resonance Imaging Outcomes in Patients With Multiple Sclerosis
journal, October 2012

Fingolimod (FTY720) Enhances Remyelination Following Demyelination of Organotypic Cerebellar Slices
journal, June 2010

An update on the biology of sphingosine 1-phosphate receptors
journal, January 2014

A practical process for the preparation of [32P]S1P and binding assay for S1P receptor ligands
journal, August 2015

High Expression of Sphingosine 1-Phosphate Receptors, S1P1 and S1P3, Sphingosine Kinase 1, and Extracellular Signal-Regulated Kinase-1/2 Is Associated with Development of Tamoxifen Resistance in Estrogen Receptor-Positive Breast Cancer Patients
journal, November 2010

A promising carbon-11-labeled sphingosine-1-phosphate receptor 1-specific PET tracer for imaging vascular injury
journal, February 2016

Fingolimod-A sphingosine-like molecule inhibits vesicle mobility and secretion in astrocytes
journal, May 2012

Molecular cloning of a novel putative G protein-coupled receptor from rat aortic smooth muscle. Downregulation of the mRNA level by the cyclic AMP messenger pathway
journal, June 1994

PET Imaging Study of S1PR1 Expression in a Rat Model of Multiple Sclerosis
journal, March 2016

Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues
journal, October 2014

Sphingosine 1-phosphate and cancer
journal, June 2010

Molecular Cloning and Functional Characterization of Murine Sphingosine Kinase
journal, September 1998

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy
journal, April 2015

Sphingolipid metabolites in inflammatory disease
journal, June 2014

Synthesis of fluorinated analogues of sphingosine-1-phosphate antagonists as potential radiotracers for molecular imaging using positron emission tomography
journal, October 2014

Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy
journal, June 2008

Sphingosine-1-phosphate receptor-1 (S1P1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease
journal, April 2016

Imaging S1P1 activation in vivo
journal, May 2015

Syntheses and in vitro evaluation of new S1PR1 compounds and initial evaluation of a lead F-18 radiotracer in rodents
journal, April 2018

Design, Synthesis, and In Vitro and In Vivo Evaluation of an ¹⁸ F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P ₁ ) PET Tracer
journal, June 2016

Sphingosine-1-Phosphate as a Ligand for the G Protein-Coupled Receptor EDG-1
journal, March 1998

Discovery and Structure–Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P ₁ )
journal, July 2016

Medicinal chemical properties of successful central nervous system drugs
journal, October 2005

Fingolimod phosphate promotes the neuroprotective effects of microglia
journal, March 2013

The Pharmacology of PEGylation: Balancing PD with PK to Generate Novel Therapeutics
journal, October 2008

FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system: FTY720 mode of action
journal, October 2009

Sphingosine-1-Phosphate Induces an Antiinflammatory Phenotype in Macrophages
journal, April 2008

Communication between host organism and cancer cells is transduced by systemic sphingosine kinase 1/sphingosine 1‐phosphate signalling to regulate tumour metastasis
journal, June 2012

Synthesis and Evaluation of Fluorinated Fingolimod (FTY720) Analogues for Sphingosine-1-Phosphate Receptor Molecular Imaging by Positron Emission Tomography
journal, April 2015

STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors
journal, November 2010

Pegylation Improves the Pharmacokinetics and Bioavailability of Small-Molecule Drugs Hydrolyzable by Esterases: A Study of Phospho-Ibuprofen
journal, July 2014

Redox Behavior of Ferrocene-Containing Rotaxane: Transposition of the Rotaxane Wheel by Redox Reaction of a Ferrocene Moiety Tethered at the End of the Axle
journal, May 2004

An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors.
journal, June 1990

Molecular imaging of multiple sclerosis: from the clinical demand to novel radiotracers
journal, April 2019

Molecular imaging of multiple sclerosis: from the clinical demand to novel radiotracers
journal, April 2019