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

1-磷酸鞘氨醇受体 1 (S1P1) 成像

• 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
• 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

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项目概要/摘要 该项目的目标是开发用于鞘氨醇成像的正电子发射断层扫描（PET）示踪剂， 1-磷酸盐受体1（S1 P1）。鞘氨醇1-磷酸（S1 P）是一种膜衍生的溶血磷脂， 通过调节5种S1 P受体亚型，在炎症性疾病中发挥重要的调节作用。S1 P1是 是这个家族中最丰富的受体之一S1 P1信号转导失调与常见的 炎症介导的疾病如涉及中枢神经系统的疾病（例如，多发性硬化[MS]）。 心血管系统（例如，动脉粥样硬化）、炎症性肠病和各种癌症。最好的 S1 P1的特征性作用是在基础和炎症条件下维持内皮屏障功能， 条件，并在炎症反应期间调节免疫细胞运输。FDA批准了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）; FTY 720对除S1 P2外的所有S1 P亚型具有高亲和力。虽然治疗的积极结果 FTY 720的RR-MS说明了该途径在慢性炎性疾病中的重要性，其机制 S1 P1通过什么途径介导不同疾病的病理变化尚不清楚。PET示踪剂， 对S1 P1的高亲和性和选择性以及合适的放射性药物性质将提供独特的成像 定量评估炎症组织中S1 P1表达的工具。这种工具的可用性将 有助于研究S1 P1在人类疾病中的作用，并可能导致诊断和治疗 范例我们放射性合成了一种已知的S1 P1抑制剂，11 C-TZ 3321（对S1 P1的IC 50 = 2.13 ± 1.63 nM，>1000 nM的S1 P2和S1 P3），用于在三种炎性疾病动物模型中进行评估，初步结果 建议11 C-TZ 3321可用于体内定量S1 P1。此外，我们还鉴定了几种先导化合物 对于未来具有高效力（S1 P1 IC 50 <10 nM）和选择性（S1 P1相对于S1 P2>100倍）的18 F标记， S1P3）。因此，为了实现TR&D1项目的目标，我们提出了五个目标中的两个具体目标， 年我们的具体目标1是将11 C-TZ 3321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S1 P1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11 C-TZ 3321 疾病和炎症性疾病患者。我们将提供前体/标准化合物和方案 包括放射化学和图像分析到我们的服务项目（SP），以帮助生成一致的 通过他们的项目。这些努力将表征S1 P1示踪剂用于PET成像的特征， 我们的研究结果将发表，以使更广泛的PET社区能够使用S1 P1 本项目开发的放射性示踪剂。