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

基本信息

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
项目类别：
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

项目摘要

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 项目概要 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 1-磷酸鞘氨醇受体 2 (S1PR2) 用于治疗多发性硬化症 (MS)、膀胱癌和其他疾病。 1-磷酸鞘氨醇 (S1P) 与五个受体超家族 S1PR1-5 结合，该受体发挥着关键的调节作用在多种人类常见疾病的病理生理过程中发挥作用。 S1PR2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S1P受体（S1PR）。 S1PR2 调节各种细胞信号传导途径，包括炎症中的细胞生长和存活、迁移和粘附，纤维化、糖尿病和癌症。尽管S1PR1被激活的星形胶质细胞和骨髓细胞上调， S1PR2 还对中枢神经系统自身免疫性疾病和其他疾病的炎症有显着影响。 S1PR2 由脑内皮细胞表达并调节小胶质细胞激活。在 MS 中，渗透物富含免疫细胞存在于脑膜中高度组织化的结构中，称为异位淋巴滤泡（ELF）模仿次级淋巴器官。 S1PR2 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性多发性硬化症 (RR-MS)；用 S1P2 拮抗剂 JTE-013 治疗动物显着减少复发后脑膜淋巴细胞的积累。 S1PR 及其信号通路也发挥着重要作用对癌细胞的命运至关重要。不同的 S1PR 亚型 (S1PR1-5) 在以下方面具有不同的功能：癌症。膀胱癌组织样本研究显示S1PR1/2亚型mRNA表达水平与膀胱尿路上皮癌的不同级别和阶段相关，表明S1PR2可以是膀胱癌的生物标志物；靶向 S1PR2 可能提供一种创新的治疗策略。在通过与我们的合作项目 (CP) 合作，我们将实现开发 C-11 或 F-18标记的S1PR2特异性PET放射性示踪剂：1）我们将设计并合成新的S1PR2配体确定它们对 S1PR2 的体外结合效力和选择性； S1PR2 配体将用 C-11 进行放射性标记或 F-18； 2) 对动物中的放射性示踪剂进行生物学评估，包括： a) 使用啮齿动物对我们的 CP 进行研究 MS 模型和膀胱癌啮齿动物模型，b) S1PR1 和 S1PR2 放射性示踪剂的评估 CP 对 MS 啮齿动物模型的自身免疫反应，c) 非人类灵长类动物的 PET 脑成像研究根据我们 CP 的反馈，对最有前途的放射性示踪剂进行放射性代谢分析。放射性标记前体和冷参考化合物，以及放射化学方案将被运送到 CP 和服务有兴趣探索 S1PR2 放射性示踪剂用于这些和其他应用的项目和其他实体。更新完成后，最有前途的 S1PR2 放射性示踪剂将准备好进行进一步的剂量测定/毒性在寻求 FDA 批准用于人类之前进行研究。