Synthesis and evaluation of 6-arylaminobenzamides as positron emission tomography imaging ligands for the sphingosine-1-phosphate-5 receptor

Timaeus E. F. Morgan; Emma K. Grant; Robert C. Shaw; Lachlan J. N. Waddell; Martyn C. Henry; Holly McErlain; Carlos J. Alcaide-Corral; Sally L. Pimlott; Adriana A. S. Tavares; Andrew Sutherland

doi:10.1039/D4MD00929K

Synthesis and evaluation of 6-arylaminobenzamides as positron emission tomography imaging ligands for the sphingosine-1-phosphate-5 receptor

Timaeus E. F. Morgan, Emma K. Grant, Robert C. Shaw, Lachlan J. N. Waddell, Martyn C. Henry, Holly McErlain, Carlos J. Alcaide-Corral, Sally L. Pimlott, Adriana A. S. Tavares, Andrew Sutherland

Research output: Contribution to journal › Article › peer-review

Abstract

The sphingosine-1-phosphate-5 (S1P5) receptor is one of the five membrane G protein-coupled receptors that are activated by the lysophospholipid, sphingosine-1-phosphate, resulting in regulation of many cellular processes. S1P5 receptors are located on oligodendrocytes and are proposed to influence oligodendrocyte physiology. Understanding S1P5 modulation during processes such as remyelination could have potential applications for demyelinating CNS disorders such as multiple sclerosis (MS). Herein, we report the synthesis and preliminary evaluation of a series of fluorinated 6-arylaminobenzamides as positron emission tomography (PET) ligands of S1P5. Pharmacokinetic screening and binding evaluation using a [35S]GTPγS assay led to the discovery of TEFM78, a selective and high affinity agonist of S1P5. Radiosynthesis of [18F]TEFM78 allowed pilot PET imaging studies in an animal model, which showed that [18F]TEFM78 can cross the blood brain barrier with good uptake in rat brain and spinal cord.

Original language	English
Journal	RSC Medicinal Chemistry
Early online date	3 Jan 2025
DOIs	https://doi.org/10.1039/D4MD00929K
Publication status	E-pub ahead of print - 3 Jan 2025

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https://xlink.rsc.org/?DOI=D4MD00929K

1 Active
2 Finished

Enabling advance imaging of synaptic function in living males and females over the course of the life-span with Positron Emission Tomography (PET)
Tavares, A. (Principal Investigator) & Grant, S. (Co-investigator)
Wellcome Trust (Rcl)
1/11/20 → 31/07/26
Project: Research
Myocardial Fibrosis And Left Ventricular Remodelling In Cardiovascular Disease
Tavares, A. (Principal Investigator), Baker, A. (Co-investigator) & Newby, D. (Co-investigator)
British Heart Foundation
1/10/19 → 30/09/24
Project: Research
Non-invasive Imaging of Human Coronary Atherothrombosis
Newby, D. (Principal Investigator)
British Heart Foundation
1/10/16 → 31/03/22
Project: Research

Edinburgh Preclinical Imaging
Moran, C. (Manager), Thomson, A. (Manager), Lennen, R. J. (Manager), Tavares, A. (Manager), Alcaide-Corral, C. J. (Manager), Morgan, T. (Other), Cranston, I. (Other) & O'Rourke, K. (Other)
Deanery of Clinical Sciences
Facility/equipment: Facility

Cite this

Morgan, T. E. F., Grant, E. K., Shaw, R. C., Waddell, L. J. N., Henry, M. C., McErlain, H., Alcaide-Corral, C. J., Pimlott, S. L., Tavares, A. A. S., & Sutherland, A. (2025). Synthesis and evaluation of 6-arylaminobenzamides as positron emission tomography imaging ligands for the sphingosine-1-phosphate-5 receptor. RSC Medicinal Chemistry. Advance online publication. https://doi.org/10.1039/D4MD00929K

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title = "Synthesis and evaluation of 6-arylaminobenzamides as positron emission tomography imaging ligands for the sphingosine-1-phosphate-5 receptor",

abstract = "The sphingosine-1-phosphate-5 (S1P5) receptor is one of the five membrane G protein-coupled receptors that are activated by the lysophospholipid, sphingosine-1-phosphate, resulting in regulation of many cellular processes. S1P5 receptors are located on oligodendrocytes and are proposed to influence oligodendrocyte physiology. Understanding S1P5 modulation during processes such as remyelination could have potential applications for demyelinating CNS disorders such as multiple sclerosis (MS). Herein, we report the synthesis and preliminary evaluation of a series of fluorinated 6-arylaminobenzamides as positron emission tomography (PET) ligands of S1P5. Pharmacokinetic screening and binding evaluation using a [35S]GTPγS assay led to the discovery of TEFM78, a selective and high affinity agonist of S1P5. Radiosynthesis of [18F]TEFM78 allowed pilot PET imaging studies in an animal model, which showed that [18F]TEFM78 can cross the blood brain barrier with good uptake in rat brain and spinal cord.",

author = "Morgan, {Timaeus E. F.} and Grant, {Emma K.} and Shaw, {Robert C.} and Waddell, {Lachlan J. N.} and Henry, {Martyn C.} and Holly McErlain and Alcaide-Corral, {Carlos J.} and Pimlott, {Sally L.} and Tavares, {Adriana A. S.} and Andrew Sutherland",

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month = jan,

day = "3",

doi = "10.1039/D4MD00929K",

language = "English",

journal = "RSC Medicinal Chemistry",

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T1 - Synthesis and evaluation of 6-arylaminobenzamides as positron emission tomography imaging ligands for the sphingosine-1-phosphate-5 receptor

AU - Morgan, Timaeus E. F.

AU - Grant, Emma K.

AU - Shaw, Robert C.

AU - Waddell, Lachlan J. N.

AU - Henry, Martyn C.

AU - McErlain, Holly

AU - Alcaide-Corral, Carlos J.

AU - Pimlott, Sally L.

AU - Tavares, Adriana A. S.

AU - Sutherland, Andrew

PY - 2025/1/3

Y1 - 2025/1/3

N2 - The sphingosine-1-phosphate-5 (S1P5) receptor is one of the five membrane G protein-coupled receptors that are activated by the lysophospholipid, sphingosine-1-phosphate, resulting in regulation of many cellular processes. S1P5 receptors are located on oligodendrocytes and are proposed to influence oligodendrocyte physiology. Understanding S1P5 modulation during processes such as remyelination could have potential applications for demyelinating CNS disorders such as multiple sclerosis (MS). Herein, we report the synthesis and preliminary evaluation of a series of fluorinated 6-arylaminobenzamides as positron emission tomography (PET) ligands of S1P5. Pharmacokinetic screening and binding evaluation using a [35S]GTPγS assay led to the discovery of TEFM78, a selective and high affinity agonist of S1P5. Radiosynthesis of [18F]TEFM78 allowed pilot PET imaging studies in an animal model, which showed that [18F]TEFM78 can cross the blood brain barrier with good uptake in rat brain and spinal cord.

AB - The sphingosine-1-phosphate-5 (S1P5) receptor is one of the five membrane G protein-coupled receptors that are activated by the lysophospholipid, sphingosine-1-phosphate, resulting in regulation of many cellular processes. S1P5 receptors are located on oligodendrocytes and are proposed to influence oligodendrocyte physiology. Understanding S1P5 modulation during processes such as remyelination could have potential applications for demyelinating CNS disorders such as multiple sclerosis (MS). Herein, we report the synthesis and preliminary evaluation of a series of fluorinated 6-arylaminobenzamides as positron emission tomography (PET) ligands of S1P5. Pharmacokinetic screening and binding evaluation using a [35S]GTPγS assay led to the discovery of TEFM78, a selective and high affinity agonist of S1P5. Radiosynthesis of [18F]TEFM78 allowed pilot PET imaging studies in an animal model, which showed that [18F]TEFM78 can cross the blood brain barrier with good uptake in rat brain and spinal cord.

U2 - 10.1039/D4MD00929K

DO - 10.1039/D4MD00929K

M3 - Article

SN - 2632-8682

JO - RSC Medicinal Chemistry

JF - RSC Medicinal Chemistry

ER -

Synthesis and evaluation of 6-arylaminobenzamides as positron emission tomography imaging ligands for the sphingosine-1-phosphate-5 receptor

Abstract

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Projects

Enabling advance imaging of synaptic function in living males and females over the course of the life-span with Positron Emission Tomography (PET)

Myocardial Fibrosis And Left Ventricular Remodelling In Cardiovascular Disease

Non-invasive Imaging of Human Coronary Atherothrombosis

Equipment

Edinburgh Preclinical Imaging

Cite this