In Vitro and In Vivo Investigation of S1PR1 Expression in the Central Nervous System Using [3H]CS1P1 and [11C]CS1P1

Jiang, Hao; Joshi, Sumit; Liu, Hui; Mansor, Syahir; Qiu, Lang; Zhao, Haiyang; Whitehead, Terence R.; Gropler, Robert J.; Wu, Gregory F.; Cross, Anne H.; Benzinger, Tammie L.S.; Shoghi, Kooresh I.; Perlmutter, Joel S.

doi:10.1021/acschemneuro.1c00492

Cited by 19 publications

(38 citation statements)

References 40 publications

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“…As expected, white matter rich regions, corpus callosum and cortical white matter had the lowest uptake (Figure 4B,C). The regional brain distribution of [ 18 F]6h matched well with our previous in vivo and in vitro characterization of S1PR1 in the CNS, 15 indicating that [ 18 F]6h has S1PR1 specific binding in the NHP brain. We further performed blocking and displacement studies using non-radioactive 6h and the FDA-approved S1PR1 modulator, ponesimod (Figure 1).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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

et al. 2023

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“…29 Therefore, in the second half of this study, we utilized our in vitro primary HBMEC model to investigate the impact of RP101075 and/or ozanimod (parent compound) on endothelial cell survival following HGD and assessed the involvement of S1PR1 activation. In the brain, S1PR1expression in peripheral immune cells 30 , neurons 31 , astrocytes 32 , microglia 33 , and endothelial cells [34][35][36] has been well documented. However, the precise S1PR1 expression profile following AIS has not been thoroughly examined.…”

Section: Introductionmentioning

confidence: 99%

Selective S1PR1 activation improves brain infarction, neurological outcome, and cerebrovascular endothelial health following experimental ischemic injury

Shi

Wendt

et al. 2023

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Sphingosine-1-phosphate receptor 1 (S1PR1) is highly expressed in endothelial cells and receptor activation plays an important role in mediating endothelial function and health, thus showing promise as a pharmacologic target for acute ischemic stroke (AIS) treatment. Here, we examined the effect of a selective S1PR1 ligand, RP101075, on infarct volume and neurological outcome in adult male mice subjected to transient middle cerebral artery occlusion (tMCAO). Concomitantly, we examined S1PR1 expression profile in the ischemic mouse brain, as well as S1PR1 expression and impact of receptor activation on human brain microvascular endothelial cell (HBMEC) proliferation and survival following hypoxia plus glucose deprivation (HGD). We observed that RP101075 administration at onset of reperfusion reduced infarct volume and lessened neurological deficits in tMCAO mice and these responses were S1PR1 dependent. Additionally, we observed that tMCAO increased brain S1PR1 protein levels and flow cytometry revealed increases in S1PR1 levels are greatest in brain endothelial cells compared to other brain cell types (astrocyte, neuron, microglia). In cultured HBMECs, RP101075 increased cell proliferation and ozanimod, parent compound of RP1010175, increased live cell count during HGD; this response was S1PR1 dependent. In conclusion, S1PR1 activation improves neuroprotection/outcome post-stroke and preserves brain endothelial cell survival following ischemia-like injury.

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“…However, a serious limitation of mRNA expression studies like that of Bowen et al (17) is that they require brain tissue which is generally not available except at autopsy. Fortunately, PET ligands for S1PR1 have been recently developed at Washington University School of Medicine (19)(20)(21)(22)(23)(24). The present study examines the differential expression of S1PR1 in the DLPFC of Type 1 and Type 2 schizophrenic patients at the protein level as a preliminary step toward the use of PET to distinguish Type 1 from Type 2 schizophrenia during life.…”

Section: Introductionmentioning

confidence: 99%

Differential Sphingosine-1-Phosphate Receptor-1 Protein Expression in the Dorsolateral Prefrontal Cortex Between Schizophrenia Type 1 and Type 2

et al. 2022

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Understanding the etiology and treatment approaches in schizophrenia is challenged in part by the heterogeneity of this disorder. One encouraging progress is the growing evidence that there are subtypes of schizophrenia. Recent in vitro findings of messenger ribonucleic acid (mRNA) gene expression on postmortem dorsolateral prefrontal cortex (DLPFC) showed that schizophrenia has two subtypes, those with a relatively normal DLPFC transcriptome (Type 1) and those with differentially expressed genes (Type 2). Sphingosine-1-phosphate receptor-1 (S1PR1) is one of the genes that was highly upregulated in Type 2 compared to Type 1 and controls. The impact of that finding is limited because it only can be confirmed through analysis of autopsy tissue, and the clinical characteristics such as symptoms severity or illness duration except for cause of death was not available from that Medical Examiner based autopsy study. However, S1PR1 has great potential because it is a target gene that can be accessed via positron emission tomography (PET) in vivo using specific radioligands (starting with [11C]CS1P1) successfully developed at our center in human brain imaging. As a preliminary study to validate this PET target in schizophrenia, S1PR1 protein expression was assessed by receptor autoradiography (ARG) using [3H]CS1P1 and immunohistochemistry (IHC) in the DLPFC from patients with schizophrenia classified as Type 1 or Type 2 based on their DLPFC transcriptomes and from controls. Our analyses demonstrate that ARG S1PR1 protein expression is significantly higher in Type 2 compared to Type 1 (p < 0.05) and controls (p < 0.05), which was consistent with previous mRNA S1PR1. These findings support the possibility that PET S1PR1 can be used as a future imaging biomarker to distinguish these subgroups of schizophrenic patients during life with obvious implications for both patient management and the design of clinical trials to validate novel pharmacologic therapies.

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In Vitro and In Vivo Investigation of S1PR1 Expression in the Central Nervous System Using [³H]CS1P1 and [¹¹C]CS1P1

Cited by 19 publications

References 40 publications

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

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

Selective S1PR1 activation improves brain infarction, neurological outcome, and cerebrovascular endothelial health following experimental ischemic injury

Differential Sphingosine-1-Phosphate Receptor-1 Protein Expression in the Dorsolateral Prefrontal Cortex Between Schizophrenia Type 1 and Type 2

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