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

1-磷酸鞘氨醇受体 1 (S1P1) 成像

• 批准号: 10480876
• 负责人: Zhude Tu
• 金额: $ 19.53万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480876
• 关键词: Acute; Adult; Affinity; Animal Model; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Back; Binding; Biodistribution; 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; 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.

R&D 1项目摘要/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)。鞘氨醇1-磷酸(S1P)是一种膜来源的溶血磷脂，它 通过调节5种S1P受体亚型，在炎症性疾病中发挥重要的调节作用。S1P1是 这个家族中最丰富的受体之一。S1P1信号的失调与常见的 炎症介导的疾病，如涉及中枢神经系统(例如，多发性硬化症[MS])。 心血管系统(如动脉粥样硬化)、炎症性肠病和各种癌症。最好的 S1P1的特征作用是在基础状态和炎症状态下维持内皮屏障功能 在炎症反应过程中调节免疫细胞的运输。FDA批准了S1P- 调节剂FTY720(Fingolimod)已广泛用于复发缓解型多发性硬化症的治疗 (RR-MS)；FTY720对除S1P2外的所有S1P亚型都有很高的亲和力。虽然治疗的积极结果是 用FTY720的RR-MS说明了这一途径在慢性炎症性疾病中的重要性，其机制 S1P1是如何介导不同疾病的病理变化的，目前还不清楚。一种PET示踪剂 S1P1的高亲和力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S1P1表达的工具。这种工具的可用性将是 促进研究S1P1在人类疾病中的作用，并可能导致诊断和治疗 范例。我们放射合成了一种已知的S1P1抑制剂11C-TZ3321(对S1P1的IC50=2.13±1.63 nM，&gt；1000 S1P2和S1P3的NM)在三种炎症性疾病动物模型中的评估，初步结果 提示11C-TZ3321可用于体内S1P1的定量。此外，我们还鉴定了几种先导化合物 对于未来具有高效价(S1P1IC50；10 nm)和选择性(S1P1比S1P2高100倍)的18F标记 和S1P3)。因此，为了实现tr&d1项目的目标，我们在五年内提出了两个具体目标。 好几年了。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，在不同的炎性动物模型中评估11C-TZ3321 在疾病和炎症性疾病的患者中。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包括到我们的服务项目(SP)中，以帮助生成一致的 通过他们的项目获取数据。这些努力将描述使用S1P1示踪剂进行PET成像的特点 炎症性疾病和我们的结果将被公布，使更广泛的PET社区能够使用S1P1 由该项目开发的放射性示踪剂。