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 该TR＆D 1的最终目标是开发一个小分子PET radiotracer，以进行体内成像 用于多发性硬化症（MS），膀胱癌和其他疾病的鞘氨氨酸1-磷酸受体2（S1PR2）。 鞘氨醇1-磷酸（S1P）与五个受体S1PR1-5的超家族结合，它们发挥关键的调节性调节 在各种常见人类疾病中的病理生理过程中的作用。 S1PR2首先是从老鼠克隆的 主动脉血管平滑肌细胞，后来被确定为高亲和力S1P受体（S1PR）。 S1PR2调节 各种细胞信号通路，包括细胞生长和生存，迁移和炎症的粘附， 纤维化，糖尿病和癌症。尽管S1PR1被活化的星形胶质细胞和髓样细胞上调，但 S1PR2还为CNS自身免疫性疾病和其他疾病的炎症做出了重大贡献。 S1PR2由脑内皮细胞表达并调节小胶质细胞活化。在MS中，浸润丰富 免疫细胞在高度组织结构的脑膜中发现，称为异位淋巴卵泡 （ELF）模仿继发性淋巴机器人。 S1PR2在MS中的关键作用是调节 免疫细胞进入脑膜。实验性自身免疫性脑脊髓炎（EAE）是啮齿动物的模型 复发重新调查MS（RR-MS）;用S1P2拮抗剂JTE-013处理动物 复发后脑膜淋巴细胞的积累。 S1PR及其信号通路也可以发挥 在癌细胞命运中的关键作用。不同的S1PR亚型（S1PR1-5）在 癌症。膀胱癌组织样品的研究表明S1PR1/2亚型mRNA表达水平 与膀胱尿路上皮癌的不同等级和阶段相关，表明S1PR2可以 成为膀胱癌的生物标志物；靶向S1PR2可能会提供创新的治疗策略。在 与我们的协作项目（CPS）合作，我们将在开发C-11或 F-18标记为S1PR2特异性PET radiotracer：1）我们将设计和合成新的S1PR2配体 确定其体外结合效力和S1PR2的选择性； S1PR2配体将用C-11进行放射性标记 或F-18； 2）对动物中放射性示例的生物学评估，包括：a）使用啮齿动物的CPS研究 MS的模型和膀胱癌的啮齿动物模型，b）评估S1PR1和S1PR2辐射示例的评估 CP，c）非人类灵长类动物中的pet脑成像研究的啮齿动物模型的自身免疫反应 基于CPS的反馈，对最有希望的放射性示踪剂的放射代谢物分析。放射性标记 前体和冷参考化合物以及放射化学协议将运送到CPS和服务 对这些应用和其他应用探索S1PR2 Radiotracers感兴趣的项目和其他实体。 续订完成后，最有希望的S1PR2 radiotracer将准备进一步剂量/毒性 在寻求FDA批准人类使用之前的研究。