# PET SPHINGOSINE-1-PHOSPHATE RECEPTOR 1 (S1PR1) RADIOTRACERS FOR MULTIPLE SCLEROSIS

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $603,264

## Abstract

A. Project summary/abstract
The goal of this project is to develop positron emission tomography (PET) tracers which quantitatively measure
the expression of the sphingosine-1-phosphate receptor 1 (S1P1). Sphingosine 1-phosphate (S1P) is a
membrane-derived lysophospholipid that plays critical regulatory roles in inflammatory diseases through
modulating five S1P receptor subtypes. S1P1 is one of the most abundant receptors in this family. Dysregulation
of S1P1 signaling is associated with inflammatory diseases in multiple organ systems, including the central
nervous system (CNS). The FDA approved S1P-modulator, FTY720 (fingolimod), has been widely used for
treatment of relapsing-remitting multiple sclerosis (RR-MS); fingolimod has high affinity to all S1P subtypes
except S1P2, but its function mainly relies on its binding with S1P1. Although positive results in treating RR-MS
with fingolimod illustrate the importance of this pathway in chronic inflammatory disease, the mechanisms by
which S1P1 mediates pathological changes in MS as well as in other diseases are still not well understood. A
PET tracer with high affinity and selectivity for S1P1 would provide a unique imaging tool to quantify S1P1
expression in inflamed tissue, thus helping physicians monitor the therapeutic efficacy of S1P1 inhibition in
individual patients by assessing changes in S1P1 expression post-treatment. To test this hypothesis, we
radiosynthesized the known S1P1 inhibitor, 11C-TZ3321 (IC50 = 2.13 ± 1.63 nM for S1P1, >1000 nM for S1P2-
5). Our preclinical data from three different animal models of inflammatory diseases suggest 11C-TZ3321 can be
used to quantify S1P1 expression in vivo. We subsequently identified several lead compounds for future 18F-
labeling that have high potency (IC50 < 20 nM for S1P1) and selectivity (IC50 >1000 nM for S1P2-5). We have
proposed two specific aims to achieve our goal. Specific aim #1 is to translate 11C-TZ3321 into clinical
investigation for proof of mechanism studies in RR-MS patients. Our multi-disciplinary team will carry out
translational 11C-TZ3321 PET studies in MS patients and healthy volunteers to determine if S1P1 expression
reflects the severity of MS and if changes of S1P1 expression reflect the therapeutic efficacy of treating MS with
fingolimod. Specific aim #2 is to develop an 18F-labeled S1P1 specific PET radiotracer. We will optimize the lead
structures of S1P1 compounds and perform in vitro binding assay to identify potent and selective compounds
that can be 18F-labeled. Upon the success of 18F-labeling, we will perform in the rat EAE model of MS will be
used for the preclinical evaluation of new 18F-labeled S1P1 PET tracers. We anticipate identifying a candidate
18F-labeled S1P1 specific radiotracer for future translational investigation of inflammatory response in human
disease.

## Key facts

- **NIH application ID:** 9973243
- **Project number:** 5R01NS103988-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Tammie Lee Smith Benzinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $603,264
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973243

## Citation

> US National Institutes of Health, RePORTER application 9973243, PET SPHINGOSINE-1-PHOSPHATE RECEPTOR 1 (S1PR1) RADIOTRACERS FOR MULTIPLE SCLEROSIS (5R01NS103988-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9973243. Licensed CC0.

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