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

R&D 1项目总结 这项研发的最终目标是开发一种小分子PET放射性示踪剂，用于活体成像 鞘氨醇-1-磷酸受体2(S1PR2)用于多发性硬化症(MS)、膀胱癌和其他疾病。 鞘氨醇-1-磷酸(S1P)结合到一个由五个受体组成的超家族，S1PR1-5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。S1PR2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的S1P受体(S1PR)。S1PR2调制 多种细胞信号通路，包括细胞生长和存活、迁移和炎症中的黏附， 纤维化、糖尿病和癌症。虽然S1PR1被激活的星形胶质细胞和髓系细胞上调， S1PR2在中枢神经系统自身免疫性疾病和其他疾病的炎症中也起重要作用。 S1PR2由脑内皮细胞表达，调节小胶质细胞的激活。在多发性硬化症中，渗透者富含 免疫细胞位于脑膜中高度组织化的结构中，称为异位淋巴滤泡。 (精灵)模仿次级淋巴器官的。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)是一种啮齿动物模型 复发-复发-多发性硬化症(RR-MS)；用S1P2拮抗剂JTE-013治疗动物显著减少 复发后脑膜淋巴细胞的聚集。S1PR及其信号通路也发挥着作用 对癌细胞的命运起着关键作用。不同的S1PR亚型(S1PR1-5)在 癌症。膀胱癌组织标本研究显示S1PR1/2亚型mRNA表达水平 S1PR2与不同分级和分期的膀胱尿路上皮癌相关 作为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……里面 与我们的合作项目(CP)合作，我们将在开发C-11或 F-18标记的S1PR2特异性PET放射性示踪剂：1)我们将设计和合成新的S1PR2配体 确定它们与S1PR2的体外结合效力和选择性；将用C-11标记S1PR2配体 或F-18；2)动物体内放射性示踪剂的生物学评价，包括：a)我们的CPS使用啮齿动物进行的研究 多发性硬化症模型和膀胱癌啮齿动物模型，b)评估S1PR1和S1PR2放射性示踪剂对 非人灵长类动物多发性硬化症啮齿动物模型自身免疫反应的CP，c)PET脑成像研究 根据我们CPS的反馈，对最有希望的放射性示踪剂进行放射代谢分析。无线电标记的 前体和冷参考化合物，以及放射化学方案将被运往CPS和服务 有兴趣为这些和其他应用探索S1PR2放射性示踪剂的项目和其他实体。 在更新完成后，最有希望的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批准人类使用之前的研究。

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.