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PET Sphingosine-1-Phosphate Receptor 1 (S1P1) radiotracer for inflammation response in multiple sclerosis

Award Number: R01NS103988
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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PET Sphingosine-1-Phosphate Receptor 1 (S1P1) radiotracer for inflammation response in multiple sclerosis - A. Project Summary/Abstract The goal of this renewal R01 application is to identify an 18F-labeled radiotracer to quantitatively measure sphingosine-1-phosphate receptor 1 (S1PR1) expression in multiple sclerosis (MS) patients. MS is associated with a lymphocyte-mediated autoimmune response that ultimately leads to repeating cycles of demyelination and repair. S1PR1 is extensively expressed on lymphocytes and endothelial cells and participates in this autoimmune inflammatory process by regulating immune cell trafficking in the brain. Currently, four S1P modulators fingolimod, siponimod, ozanimod, and ponesimod have been approved by FDA for treating MS, but the pathophysiologic mechanism of S1PR1 in MS is still not well understood. Positron emission tomography (PET) investigating S1PR1 function in MS and other diseases is limited by the lack of a clinically suitable radiotracer. To address this urgent clinical need, our team successfully transferred [11C]CS1P1, a C-11 S1PR1 radiotracer into clinical investigation. Our human study data confirm that liver is the critical organ for radiation dose absorption and that [11C]CS1P1 is safe for patient who receives a dose of up to 740 MBq (20 mCi). Our proof of concept brain studies showed higher uptake of [11C]CS1P1 in gray matter than in white matter, consistent with S1PR1 mRNA expression in the normal human brain. In MS patients, we observed increased [11C]CS1P1 uptake within both brain lesions and normal appearing white matter (WM). These results are consistent with extant evidence of inflammatory infiltrate in both the brain lesions and normal appearing WM in MS. Together, our data suggest that PET measurement of S1PR1 protein expression could provide a unique method to detect neuroinflammation and response in MS patients. Our initial radiometabolite analysis of human plasma discovered a lipophilic radiometabolite post injection of [11C]CS1P1 and led to initial concerns. However, we recently confirmed the molecular structure of the radiometabolite, and radiometabolite analysis of the rat brain and plasma post-injection of the radiotracer and PET brain studies of the F-18 labeled radiometaobolite demonstrated the radiometabolite does not enter into the brain. Additionally, our team has synthesized ~120 new structurally diverse S1PR1 ligands, and ~30 of them are highly potent (IC50 < 20 nM) and selective for S1PR1. To date, our preliminary data indicate that three F-18 radiotracers are promise for S1PR1 imaging, two of them are F-18 labeled using different procedures and are anticipated to have different pathway compared to [11C]CS1P1. Therefore, in this renewal phase, we will leverage our recent experience with [11C]CS1P1 and develop and transfer an 18F-labeled S1PR1 tracer for clinical investigation. We propose two specific aims: 1) Identify and transfer the most promising 18F-labeled S1PR1 tracer into human investigations. 2) Implement PET imaging human studies in healthy controls and MS patients. When the completion of this application, a clinical suitable S1PR1 18F-radiotracer will be identified and ready to implement for MS and other inflammatory diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $625,133 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	5/29/2025	NON-COMPETING CONTINUATION	$625,133
2025	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	2/12/2025	COMPETING CONTINUATION	$3,522
2025	2021	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/12/2025	NON-COMPETING CONTINUATION	-$3,522
														Subtotal = $625,133

Issue Date FY: 2024 ( Subtotal = $604,725 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	6/27/2024	NON-COMPETING CONTINUATION	$604,725
														Subtotal = $604,725

Issue Date FY: 2023 ( Subtotal = $640,904 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	6/30/2023	COMPETING CONTINUATION	$640,904
														Subtotal = $640,904

Issue Date FY: 2021 ( Subtotal = $594,515 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/29/2021	NON-COMPETING CONTINUATION	$594,515
														Subtotal = $594,515

Issue Date FY: 2020 ( Subtotal = $603,264 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/30/2020	NON-COMPETING CONTINUATION	$603,264
														Subtotal = $603,264

Issue Date FY: 2019 ( Subtotal = $610,946 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	7/16/2019	NON-COMPETING CONTINUATION	$0
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/5/2019	NON-COMPETING CONTINUATION	$610,946
														Subtotal = $610,946

Issue Date FY: 2018 ( Subtotal = $552,813 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/20/2018	NON-COMPETING CONTINUATION	$552,813
														Subtotal = $552,813

Issue Date FY: 2017 ( Subtotal = $478,679 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/22/2017	NEW	$478,679
														Subtotal = $478,679

Grand Total All Awards = $4,710,979

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PET Sphingosine-1-Phosphate Receptor 1 (S1P1) radiotracer for inflammation response in multiple sclerosis

Award Number: R01NS103988

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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