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.

Public Health Relevance

Multiple sclerosis (MS) results from an immune-response which triggers inflammation and demyelination in the central nervous system (CNS). There are an estimated 450,000 MS patients in United States alone. Unlike many other neurodegenerative diseases, MS affects mainly young adults; the lifetime direct and indirect costs estimated at $1.2 million per patient. Fingolimod, a sphingosine-1-phosphate receptor 1 (S1PR1) inhibitor has been using for treatment of relapsing-remitting MS (RRMS) and show good efficacy. The S1PR1 PET imaging agents will be a valuable clinical tool for monitoring the progression of MS and evaluate the efficacy of treating RRMS and other inflammatory diseases using S1PR1 inhibition strategy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Babcock, Debra J
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Washington University
Schools of Medicine
Saint Louis
United States
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Yue, Xuyi; Dhavale, Dhruva D; Li, Junfeng et al. (2018) Design, synthesis, and in vitro evaluation of quinolinyl analogues for ?-synuclein aggregation. Bioorg Med Chem Lett 28:1011-1019
Yue, Xuyi; Luo, Zonghua; Liu, Hui et al. (2018) Radiosynthesis and evaluation of a fluorine-18 labeled radioligand targeting vesicular acetylcholine transporter. Bioorg Med Chem Lett 28:3425-3430
Jin, Hongjun; Yue, Xuyi; Liu, Hui et al. (2018) Kinetic modeling of [18 F]VAT, a novel radioligand for positron emission tomography imaging vesicular acetylcholine transporter in non-human primate brain. J Neurochem 144:791-804
Jin, Hongjun; Han, Junbin; Resing, Derek et al. (2018) Synthesis and in vitro characterization of a P2X7 radioligand [123I]TZ6019 and its response to neuroinflammation in a mouse model of Alzheimer disease. Eur J Pharmacol 820:8-17
Luo, Zonghua; Rosenberg, Adam J; Liu, Hui et al. (2018) Syntheses and in vitro evaluation of new S1PR1 compounds and initial evaluation of a lead F-18 radiotracer in rodents. Eur J Med Chem 150:796-808
Liu, Chunling; Liu, Hui; Jin, Hongjun et al. (2018) Cholinergic imbalance in lumbar spinal cord of a rat model of multiple sclerosis. J Neuroimmunol 318:29-35
Liu, Hui; Jin, Hongjun; Han, Junbin et al. (2018) Upregulated Sphingosine 1-Phosphate Receptor 1 Expression in Human and Murine Atherosclerotic Plaques. Mol Imaging Biol 20:448-456
Liu, Hui; Jin, Hongjun; Luo, Zonghua et al. (2018) In Vivo Characterization of Two 18F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains. ACS Chem Neurosci 9:1066-1073