TY - JOUR
T1 - Discovery of a Promising Fluorine-18 Positron Emission Tomography Radiotracer for Imaging Sphingosine-1-Phosphate Receptor 1 in the Brain
AU - Qiu, Lin
AU - Jiang, Hao
AU - Zhou, Charles
AU - Wang, Jinzhi
AU - Yu, Yanbo
AU - Zhao, Haiyang
AU - Huang, Tianyu
AU - Gropler, Robert
AU - Perlmutter, Joel S.
AU - Benzinger, Tammie L.S.
AU - Tu, Zhude
N1 - Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/4/13
Y1 - 2023/4/13
N2 - Sphingosine-1-phosphate receptor 1 (S1PR1) is recognized as a novel therapeutic and diagnostic target in neurological disorders. We recently transferred the S1PR1 radioligand [11C]CS1P1 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 6h is potent (IC50 = 8.7 nM) and selective for S1PR1. [18F]6h 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 [18F]6h in vivo. Radiometabolite analysis confirmed no radiometabolite of [18F]6h entered into the brain to confound the PET measurement. In summary, [18F]6h is a promising radioligand to image S1PR1 and worth translational clinical investigation for humans with brain disorders.
AB - Sphingosine-1-phosphate receptor 1 (S1PR1) is recognized as a novel therapeutic and diagnostic target in neurological disorders. We recently transferred the S1PR1 radioligand [11C]CS1P1 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 6h is potent (IC50 = 8.7 nM) and selective for S1PR1. [18F]6h 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 [18F]6h in vivo. Radiometabolite analysis confirmed no radiometabolite of [18F]6h entered into the brain to confound the PET measurement. In summary, [18F]6h is a promising radioligand to image S1PR1 and worth translational clinical investigation for humans with brain disorders.
UR - http://www.scopus.com/inward/record.url?scp=85150444532&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.2c01752
DO - 10.1021/acs.jmedchem.2c01752
M3 - Article
C2 - 36926861
AN - SCOPUS:85150444532
SN - 0022-2623
VL - 66
SP - 4671
EP - 4688
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -