Discovery of a Promising Fluorine-18 Positron Emission Tomography Radiotracer for Imaging Sphingosine-1-Phosphate Receptor 1 in the Brain

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2023 Mar 17

PMID 36926861

Authors

Lin Qiu

Hao Jiang

Charles Zhou

Jinzhi Wang

Yanbo Yu

Haiyang Zhao

Tianyu Huang

Robert Gropler

Joel S Perlmutter

Tammie L S Benzinger

Zhude Tu

Affiliations

Soon will be listed here.

Abstract

Sphingosine-1-phosphate receptor 1 (S1PR1) is recognized as a novel therapeutic and diagnostic target in neurological disorders. We recently transferred the S1PR1 radioligand [C] into clinical investigation for multiple sclerosis. Herein, we reported the design, synthesis and evaluation of novel F-18 S1PR1 radioligands. We combined the structural advantages of our two lead S1PR1 radioligands and synthesized 14 new S1PR1 compounds, then performed F-18 radiochemistry on the most promising compounds. Compound is potent (IC = 8.7 nM) and selective for S1PR1. [F] exhibited a high uptake in macaque brain (SUV > 3.0) and favorable brain washout pharmacokinetics in positron emission tomography (PET) study. PET blocking and displacement studies confirmed the specificity of [F] . Radiometabolite analysis confirmed no radiometabolite of [F] entered into the brain to confound the PET measurement. In summary, [F] is a promising radioligand to image S1PR1 and worth translational clinical investigation for humans with brain disorders.

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