权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

用于多发性硬化症的 PET 1-磷酸鞘氨醇受体 1 (S1PR1) 放射性示踪剂

基本信息

批准号：
10226102
负责人：
Tammie Lee Smith Benzinger
金额：
$ 59.45万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226102
关键词：
Acute Affect Affinity Aftercare Animal Model Apolipoprotein E Autoimmune Autoimmune Responses Autopsy Basic Science Binding Biodistribution Biological Assay Brain Cells Chemistry Clinical Clinical Distribution Cyclic GMP Data Demyelinations Development Direct Costs Disease Dose Drug Targeting Effectiveness Endothelial Cells Evaluation Experimental Autoimmune Encephalomyelitis FDA approved Facilities and Administrative Costs Family Female Future Goals Half-Life Human Hyperplasia Image Imaging Device Immune Immune response In Vitro Inflammation Inflammatory Inflammatory Response Injections Injury Institutional Review Boards Investigation Investigational New Drug Application Label Lead Lymphocyte Lysophospholipids Measures Mediating Membrane Methods Modeling Monitor Multiple Sclerosis Mus Neuraxis Neurodegenerative Disorders No-Observed-Adverse-Effect Level Pathogenesis Pathologic Pathway interactions Patients Physicians Plasma Play Positron-Emission Tomography Process Production Radiolabeled Radiopharmaceuticals Rattus Relapse Relapsing-Remitting Multiple Sclerosis Rodent Role Running Safety Sampling Severities Signal Transduction Site Sphingosine-1-Phosphate Receptor Structure Testing Time Tissues Toxic effect Toxicity Tests Tracer Translating Treatment Efficacy United States Up-Regulation Validation body system chronic inflammatory disease clinical investigation cost estimate dosimetry efficacy evaluation femoral artery good laboratory practice healthy volunteer human disease human imaging human subject imaging agent imaging study in vivo individual patient inhibitor/antagonist lead optimization male metabolic abnormality assessment multidisciplinary multiple sclerosis patient pre-clinical preclinical evaluation radiation absorbed dose radioligand radiotracer receptor receptor expression relapse patients repaired research study response sphingosine 1-phosphate success tool trafficking uptake vascular inflammation young adult

项目摘要

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.

A.项目概要/摘要该项目的目标是开发正电子发射断层扫描（PET）示踪剂，鞘氨醇-1-磷酸受体1（S1 P1）的表达。鞘氨醇1-磷酸（S1 P）是一种膜源性溶血磷脂，在炎症性疾病中起着关键的调节作用，调节五种S1 P受体亚型。S1 P1是该家族中最丰富的受体之一。失调 S1 P1信号传导与多器官系统的炎症性疾病有关，包括中枢神经系统。神经系统（CNS）。FDA批准的S1 P-调节剂FTY 720（芬戈莫德）已广泛用于治疗复发-缓解型多发性硬化症（RR-MS）;芬戈莫德对所有S1 P亚型具有高亲和力除S1 P2外，其功能主要依赖于与S1 P1的结合。虽然治疗RR-MS的结果是积极的，与芬戈莫德的研究说明了该途径在慢性炎症性疾病中的重要性， S1 P1介导MS以及其他疾病的病理变化仍然没有很好的理解。一对S1 P1具有高亲和力和选择性的PET示踪剂将提供独特的成像工具来定量S1 P1 表达，从而帮助医生监测S1 P1抑制在炎症组织中的治疗效果。通过评估治疗后S1 P1表达的变化来评估个体患者。为了验证这个假设，我们放射性合成已知的S1 P1抑制剂11 C-TZ 3321（对于S1 P1，IC 50 = 2.13 ± 1.63 nM，对于S1 P2-TZ 3321，IC 50>1000 nM）。（五）。我们从三种不同的炎症性疾病动物模型中获得的临床前数据表明，11 C-TZ 3321可以用于治疗炎症性疾病。用于定量体内S1 P1表达。我们随后确定了未来18F的几种先导化合物- 具有高效力（对于S1 P1，IC 50 < 20 nM）和选择性（对于S1 P2 -5，IC 50>1000 nM）的标记。我们有提出了两个具体目标来实现我们的目标。具体目标1是将11 C-TZ 3321转化为临床 RR-MS患者机制研究证据的调查。我们的多学科团队将执行在MS患者和健康志愿者中进行的11 C-TZ 3321翻译PET研究，以确定S1 P1表达反映了MS的严重程度，并且如果S1 P1表达的变化反映了用芬戈莫德具体目标#2是开发18F标记的S1 P1特异性PET放射性示踪剂。我们将优化铅 S1 P1化合物的结构，并进行体外结合试验，以鉴定有效和选择性的化合物可以被18F标记。在18F标记成功后，我们将在MS的大鼠EAE模型中进行用于新的18F标记的S1 P1 PET示踪剂的临床前评价。我们预计会找到一个候选人 ~（18）F标记的S1 P1特异性放射性示踪剂用于人类炎症反应的未来翻译研究疾病