Development of PET radiotracer for imaging sphingosine-1-phosphate receptor 2 (S1PR2)

开发用于 1-磷酸鞘氨醇受体 2 (S1PR2) 成像的 PET 放射性示踪剂

• 批准号: 10715914
• 负责人: Zhude Tu
• 金额: $ 25.53万
• 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 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715914
• 关键词: Acute; Adhesions; Affinity; Animals; Aorta; Astrocytes; Autoimmune Responses; Autoradiography; B-Cell Activation; Binding; Biodistribution; Biological; Biological Markers; Bladder Neoplasm; Blood; Brain; Brain imaging; CNS autoimmune disease; Cell Survival; Cells; Characteristics; Chronic Kidney Failure; Collaborations; Communities; Control Animal; Development; Diabetes Mellitus; Disease; Drug Kinetics; Drug or chemical Tissue Distribution; Enzyme-Linked Immunosorbent Assay; Evaluation; Experimental Autoimmune Encephalomyelitis; Feedback; Fibrosis; Funding; Genetic Transcription; Goals; High Pressure Liquid Chromatography; Human; Image; Immune; ImmunoPET; Immunohistochemistry; In Vitro; Infection; Infiltration; Inflammation; Inflammatory Bowel Diseases; Institution; Instruction; Label; Ligands; Lymphocyte; Lymphoid Follicle; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Meningeal; Meninges; Messenger RNA; Modeling; Multiple Sclerosis; Mus; Myeloid Cells; Names; Plasma; Play; Positron-Emission Tomography; Process; Protocols documentation; Publishing; Radiochemistry; Radiolabeled; Rattus; Recurrence; Relapse; Research; Resources; Rodent; Rodent Model; Role; Sampling; Services; Signal Pathway; Smooth Muscle Myocytes; Specificity; Sphingosine-1-Phosphate Receptor; Stains; Therapeutic; Tissue Sample; Tissues; Toxic effect; Tracer; Translations; Vascular Smooth Muscle; Western Blotting; Work; antagonist; bladder Carcinoma; bladder transitional cell carcinoma; brain endothelial cell; cancer cell; cancer therapy; cell growth; clinical investigation; design; dosimetry; first-in-human; glial activation; human data; human disease; imaging biomarker; imaging science; imaging study; immune cell infiltrate; in vivo; in vivo imaging; inhibitor; innovation; interest; mRNA Expression; migration; neuroinflammation; nonhuman primate; novel; organizational structure; pre-clinical; radiotracer; receptor; secondary lymphoid organ; small molecule; sphingosine 1-phosphate; tumor; uptake

TR&D 1 Project Summary The ultimate goal of this TR&D 1 is to develop a small molecule PET radiotracer for in vivo imaging of Sphingosine-1-phosphate receptor 2 (S1PR2) for multiple sclerosis (MS), bladder cancer, and other diseases. Sphingosine-1-phosphate (S1P) binds to a superfamily of five receptors, S1PR1-5, which play critical regulatory roles in pathophysiological processes in a variety of common human diseases. S1PR2 was first cloned from rat aortic vascular smooth muscle cells and later identified as a high affinity S1P receptor (S1PR). S1PR2 modulates various cellular signaling pathways including cell growth and survival, migration, and adhesion in inflammation, fibrosis, diabetes, and cancer. Although S1PR1 is up-regulated by activated astrocytes and myeloid cells, S1PR2 also contributes significantly to inflammation in CNS autoimmune diseases and other diseases. S1PR2 is expressed by brain endothelial cells and modulates microglial activation. In MS, infiltrates rich in immune cells are found in the meninges within highly organized structures named ectopic lymphoid follicles (ELF) that mimic secondary lymphoid organs. A key role for S1PR2 in MS is regulating the infiltration of immune cells into the meninges. Experimental autoimmune encephalomyelitis (EAE) is a rodent model of relapsing-recurring-MS (RR-MS); treatment of animals with the S1P2 antagonist JTE-013 significantly diminishes the accumulation of meningeal lymphocytes following relapses. S1PRs and their signaling pathways also play a critical role in the destiny of cancer cells. The different S1PR subtypes (S1PR1-5) have different functions in cancer. Studies of bladder cancer tissue samples showed that S1PR1/2 subtype mRNA expression level correlates with different grades and stages of bladder urothelial carcinoma, suggesting that S1PR2 could be a biomarker for bladder carcinoma; targeting S1PR2 may provide an innovative therapeutic strategy. In partnership with our Collaborative Projects (CPs) we will accomplish two specific aims in developing a C-11 or F-18 labeled S1PR2 specific PET radiotracer: 1) We will design and synthesize new S1PR2 ligands then determine their in vitro binding potency and selectivity for S1PR2; S1PR2 ligands will be radiolabeled with C-11 or F-18; 2) Biological evaluation of the radiotracers in animals including: a) studies with our CPs using rodent models of MS and a rodent model of bladder cancer, b) evaluation of both S1PR1 and S1PR2 radiotracers for autoimmune response for in rodent model of MS by a CP, c) PET brain imaging study in nonhuman primates and radiometabolite analysis of the most promising radiotracer based on feedback from our CPs. Radiolabeled precursors and cold reference compounds, and the radiochemistry protocols will be shipped to CPs and Service Projects and other entities that are interested at exploring S1PR2 radiotracers for these and other applications. Upon completion of this renewal, the most promising S1PR2 radiotracer will be ready for further dosimetry/toxicity studies prior to seeking FDA approval for human use.

TR&D 1项目摘要 这个TR&D 1的最终目标是开发一种小分子PET放射性示踪剂，用于体内成像， 鞘氨醇-1-磷酸受体2（S1 PR 2）用于多发性硬化症（MS）、膀胱癌和其他疾病。 鞘氨醇-1-磷酸（S1 P）与五种受体的超家族S1 PR 1 -5结合，这些受体起着关键的调节作用， 在多种常见人类疾病的病理生理过程中的作用。S1 PR 2基因首次从大鼠中克隆 主动脉血管平滑肌细胞，后来被鉴定为高亲和力S1 P受体（S1 PR）。S1 PR 2调节 各种细胞信号传导途径，包括细胞生长和存活、迁移和炎症中的粘附， 纤维化糖尿病和癌症尽管S1 PR 1被活化的星形胶质细胞和髓样细胞上调， S1 PR 2还显著促进CNS自身免疫性疾病和其他疾病中的炎症。 S1 PR 2由脑内皮细胞表达并调节小胶质细胞活化。在MS中， 免疫细胞存在于脑膜中高度组织化的结构内，称为异位淋巴滤泡 (ELF)模仿次级淋巴器官S1 PR 2在MS中的一个关键作用是调节 免疫细胞进入脑膜实验性自身免疫性脑脊髓炎（EAE）是一种啮齿动物模型， 复发-复发-MS（RR-MS）;用S1 P2拮抗剂JTE-013治疗动物显著减少 复发后脑膜淋巴细胞的积聚。S1 PRs及其信号通路也发挥着重要作用。 在癌细胞的命运中起着关键作用。不同的S1 PR亚型（S1 PR 1 -5）在免疫调节中具有不同的功能。 癌膀胱癌组织标本中S1 PR 1/2亚型mRNA表达水平 与膀胱尿路上皮癌的不同分级和分期相关，提示S1 PR 2可能 成为膀胱癌的生物标志物;靶向S1 PR 2可能提供一种创新的治疗策略。在 与我们的合作项目（CP）的伙伴关系，我们将实现两个具体目标，在发展C-11或 F-18标记的S1 PR 2特异性PET放射性示踪剂：1）我们将设计并合成新的S1 PR 2配体， 测定其体外结合效力和对S1 PR 2的选择性; S1 PR 2配体将用C-11放射性标记 或F-18; 2）放射性示踪剂在动物中的生物学评价，包括：a）使用啮齿动物进行的CP研究 B）评估S1 PR 1和S1 PR 2放射性示踪剂用于MS模型和膀胱癌啮齿动物模型， 通过CP在MS啮齿动物模型中形成的自身免疫应答，c）在非人灵长类动物中的PET脑成像研究 和放射性代谢分析的最有前途的放射性示踪剂的基础上反馈我们的CP。放射标记 前体和冷参比化合物以及放射化学方案将被运送到CP和服务部门 有兴趣探索S1 PR 2放射性示踪剂的项目和其他实体。 在完成此次更新后，最有前途的S1 PR 2放射性示踪剂将准备用于进一步的剂量测定/毒性 在寻求FDA批准用于人类之前进行研究。