Imaging the Sphingosine-1-Phosphate Receptor 1 (S1P1)

1-磷酸鞘氨醇受体 1 (S1P1) 成像

基本信息

批准号：
10254232
负责人：
Zhude Tu
金额：
$ 19.14万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254232
关键词：
Acute Adult Affinity Animal Model Apolipoprotein E Arterial Fatty Streak Atherosclerosis Back Binding Biodistribution Biological Biology Blood Vessels Cancer Model Cardiovascular system Cells Clinical Communities Cyclic GMP Data Development Diagnostic Disease Dose Endothelium Evaluation Experimental Autoimmune Encephalomyelitis FDA approved Family Female Future Goals Grant Half-Life Hematoxylin and Eosin Staining Method High Pressure Liquid Chromatography Human Hyperplasia Image Image Analysis Imaging Device Immune Immunofluorescence Immunologic Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Injections Injury Institutional Review Boards Investigation Label Lead Ligands Lysophospholipids Malignant Neoplasms Mediating Membrane Modeling Multiple Sclerosis Mus Neuraxis No-Observed-Adverse-Effect Level Pathologic Pathway interactions Patients Peripheral arterial disease Plasma Play Positron-Emission Tomography Production Property Protocols documentation Publishing Radiochemistry Radiopharmaceuticals Rattus Relapsing-Remitting Multiple Sclerosis Resources Rodent Role Safety Sampling Services Signal Transduction Site Sphingosine-1-Phosphate Receptor Stains Therapeutic Time Tissues Toxic effect Toxicity Tests Tracer Translating Up-Regulation Work body system chronic inflammatory disease clinical investigation design dosimetry feasibility testing femoral artery good laboratory practice human disease human imaging imaging study in vivo inhibitor/antagonist male multiple sclerosis patient preclinical evaluation radiation absorbed dose radioligand radiotracer receptor response scale up sphingosine 1-phosphate tool trafficking

项目摘要

TR&D 1 Project summary/abstract The goal of this project is to develop positron emission tomography (PET) tracers for imaging the sphingosine- 1-phosphate receptor 1 (S1P1). Sphingosine 1-phosphate (S1P) is a membrane-derived lysophospholipid which plays critical regulatory roles in inflammatory disease through modulating five S1P receptor subtypes. S1P1 is one of the most abundant receptors in this family. Dysregulation of S1P1 signaling is associated with common inflammation-mediated diseases such as involving the central nervous system (e.g., multiple sclerosis [MS]). The cardiovascular system (e.g., atherosclerosis), inflammatory bowel disease and various cancers. The best characterized roles of S1P1 are maintaining endothelial barrier function under both basal and inflammatory conditions, and regulating immune cell trafficking during inflammatory response. The FDA approved S1P- modulator, FTY720 (fingolimod), has been widely used for treatment of relapsing-remitting multiple sclerosis (RR-MS); FTY720 has high affinity for all S1P subtypes except S1P2. Although the positive results in treating RR-MS with FTY720 illustrate the importance of this pathway in chronic inflammatory disease, the mechanism by which S1P1 mediates pathological changes in different diseases is not well understood. A PET tracer with high affinity and selectivity for S1P1 and suitable radiopharmaceutical properties would provide a unique imaging tool to assess quantitatively S1P1 expression in inflammatory tissues. The availability of such a tool would facilitate the study of the role of S1P1 in human disease and potentially lead to diagnostic and therapeutic paradigms. We radiosynthesized a known S1P1 inhibitor, 11C-TZ3321 (IC50 = 2.13 ± 1.63 nM for S1P1, >1000 nM for S1P2 and S1P3) for evaluation in three animal models of inflammatory disease, preliminary results suggest 11C-TZ3321 can be used to quantify S1P1 in vivo. In addition, we also identified several lead compounds for future 18F-labeling that have high potency (S1P1 IC50<10 nM) and selectivity (>100-fold for S1P1 versus S1P2 and S1P3). Therefore, to achieve the goal of the TR&D1 project, we have proposed two specific aims within five years. Our specific aim 1 is to translate 11C-TZ3321 into initial proof of mechanism studies in RR-MS patients. Our specific aim 2 is to develop an 18F-labeled S1P1 specific PET tracer. To accomplish the specific aims, we will work with our collaborative projects (CPs) to evaluate 11C-TZ3321 in different animal models of inflammatory disease and in patients with inflammatory disease. We will provide precursor/standard compounds and protocols including radiochemistry and image analysis to our service projects (SPs) to assist with generating consistent data through their projects. These efforts will characterize the use of an S1P1 tracer for PET imaging of inflammatory disease and our results will be published to enable the wider PET community to use the S1P1 radiotracer developed by this project.

TR&D 1 项目总结/摘要该项目的目标是开发用于对鞘氨醇进行成像的正电子发射断层扫描 (PET) 示踪剂 1-磷酸受体 1 (S1P1) 1-磷酸鞘氨醇 (S1P) 是一种膜源性溶血磷脂。 S1P1 通过调节五种 S1P 受体亚型在炎症性疾病中发挥关键的调节作用。该家族中最丰富的受体之一与常见的 S1P1 信号传导失调有关。炎症介导的疾病，例如涉及中枢神经系统的疾病（例如多发性硬化症 [MS]）。心血管系统（例如动脉粥样硬化）、炎症性肠病和各种癌症最好。 S1P1 的典型作用是在基础和炎症条件下维持内皮屏障功能 FDA 批准了 S1P-。调节剂 FTY720（芬戈莫德）已广泛用于治疗复发缓解型多发性硬化症 (RR-MS)；FTY720对除S1P2之外的所有S1P亚型具有高亲和力。使用 FTY720 进行 RR-MS 说明了该通路在慢性炎症性疾病中的重要性，其机制 S1P1 通过何种方式介导不同疾病的病理变化尚不清楚。对 S1P1 的高亲和力和选择性以及合适的放射性药物特性将提供独特的成像定量评估炎症组织中 S1P1 表达的工具。促进 S1P1 在人类疾病中的作用的研究，并有可能导致诊断和治疗我们放射合成了一种已知的 S1P1 抑制剂 11C-TZ3321（S1P1 的 IC50 = 2.13 ± 1.63 nM，>1000） nM（S1P2 和 S1P3），用于在三种炎症性疾病动物模型中进行评估，初步结果建议 11C-TZ3321 可用于体内定量 S1P1 此外，我们还鉴定了几种先导化合物。用于未来具有高效力 (S1P1 IC50<10 nM) 和选择性（S1P1 与 S1P2 相比 >100 倍）的 18F 标记因此，为了实现TR&D1项目的目标，我们在5年内提出了两个具体目标。我们的具体目标 1 是将 11C-TZ3321 转化为 RR-MS 患者机制研究的初步证据。我们的具体目标 2 是开发 18F 标记的 S1P1 特异性 PET 示踪剂为了实现具体目标，我们。将与我们的合作项目 (CP) 合作，在不同的炎症动物模型中评估 11C-TZ3321 我们将提供前体/标准化合物和方案。将放射化学和图像分析纳入我们的服务项目 (SP)，以协助生成一致的结果这些工作将描述 S1P1 示踪剂在 PET 成像中的使用。炎症性疾病，我们的结果将被发表，以使更广泛的 PET 社区能够使用 S1P1 该项目开发的放射性示踪剂。