PET Sphingosine-1-Phosphate Receptor 1 (S1P1) radiotracer for inflammation response in multiple sclerosis

A.项目概要/摘要 此次更新R 01应用的目标是识别18F标记的放射性示踪剂，以定量测量 多发性硬化（MS）患者中1-磷酸鞘氨醇受体1（S1 PR 1）表达。MS相关 淋巴细胞介导的自身免疫反应最终导致反复的脱髓鞘循环 和修复。S1 PR 1在淋巴细胞和内皮细胞上广泛表达，并参与了这一过程。 通过调节大脑中的免疫细胞运输来调节自身免疫性炎症过程。目前，四个S1 P 调节剂芬戈莫德、辛波莫德、奥扎尼莫德和波奈莫德已被FDA批准用于治疗MS，但 S1 PR 1在MS中的病理生理机制仍不清楚。正电子发射断层扫描 (PET)研究S1 PR 1在MS和其他疾病中的功能受到缺乏临床合适的 放射性示踪剂为了解决这一紧迫的临床需求，我们的团队成功地转移了[11 C] CS 1 P1，一种C-11 S1 PR 1 放射性示踪剂用于临床研究。我们的人体研究数据证实，肝脏是辐射的关键器官 剂量吸收，并且[11 C] CS 1 P1对于接受高达740 MBq（20 mCi）剂量的患者是安全的。我们 脑概念验证研究显示，灰质中[11 C] CS 1 P1的摄取高于白色物质，这与 S1 PR 1 mRNA在正常人脑中的表达。在MS患者中，我们观察到[11 C] CS 1 P1增加， 在脑病变和正常外观的白色物质（WM）内的摄取。这些结果是一致 在MS的脑损伤和正常表现的WM中存在炎性浸润的证据。总之， 我们的数据表明，PET测量S1 PR 1蛋白表达可以提供一种独特的方法， MS患者的神经炎症和反应。我们对人体血浆的初步放射性代谢物分析 在注射[11 C] CS 1 P1后发现了亲脂性放射性代谢物，并引起了最初的关注。但我们 最近证实了放射性代谢物的分子结构，并对大鼠大脑进行了放射性代谢物分析 放射性示踪剂注射后的血浆和F-18标记的放射性代谢物的PET脑研究 证明了放射性代谢物不会进入大脑此外，我们的团队还合成了约120个 新的结构多样的S1 PR 1配体，其中约30种是高度有效的（IC 50 < 20 nM）和选择性的， S1 PR 1。迄今为止，我们的初步数据表明，三种F-18放射性示踪剂有望用于S1 PR 1成像，两种 其中使用不同的程序标记F-18，预计与 [11C]CS1P1。因此，在此更新阶段，我们将利用我们最近在[11 C] CS 1 P1方面的经验， 开发并转移18F标记的S1 PR 1示踪剂用于临床研究。我们提出两个具体目标：1） 识别并将最有希望的18F标记的S1 PR 1示踪剂转移到人类研究中。2)实施PET 在健康对照和MS患者中进行的成像人类研究。当完成此申请后，临床 合适S1 PR 118 F-放射性示踪剂将被鉴定并准备用于MS和其它炎性疾病。

A. Project Summary/Abstract The goal of this renewal R01 application is to identify an 18F-labeled radiotracer to quantitatively measure sphingosine-1-phosphate receptor 1 (S1PR1) expression in multiple sclerosis (MS) patients. MS is associated with a lymphocyte-mediated autoimmune response that ultimately leads to repeating cycles of demyelination and repair. S1PR1 is extensively expressed on lymphocytes and endothelial cells and participates in this autoimmune inflammatory process by regulating immune cell trafficking in the brain. Currently, four S1P modulators fingolimod, siponimod, ozanimod, and ponesimod have been approved by FDA for treating MS, but the pathophysiologic mechanism of S1PR1 in MS is still not well understood. Positron emission tomography (PET) investigating S1PR1 function in MS and other diseases is limited by the lack of a clinically suitable radiotracer. To address this urgent clinical need, our team successfully transferred [11C]CS1P1, a C-11 S1PR1 radiotracer into clinical investigation. Our human study data confirm that liver is the critical organ for radiation dose absorption and that [11C]CS1P1 is safe for patient who receives a dose of up to 740 MBq (20 mCi). Our proof of concept brain studies showed higher uptake of [11C]CS1P1 in gray matter than in white matter, consistent with S1PR1 mRNA expression in the normal human brain. In MS patients, we observed increased [11C]CS1P1 uptake within both brain lesions and normal appearing white matter (WM). These results are consistent with extant evidence of inflammatory infiltrate in both the brain lesions and normal appearing WM in MS. Together, our data suggest that PET measurement of S1PR1 protein expression could provide a unique method to detect neuroinflammation and response in MS patients. Our initial radiometabolite analysis of human plasma discovered a lipophilic radiometabolite post injection of [11C]CS1P1 and led to initial concerns. However, we recently confirmed the molecular structure of the radiometabolite, and radiometabolite analysis of the rat brain and plasma post-injection of the radiotracer and PET brain studies of the F-18 labeled radiometaobolite demonstrated the radiometabolite does not enter into the brain. Additionally, our team has synthesized ~120 new structurally diverse S1PR1 ligands, and ~30 of them are highly potent (IC50 < 20 nM) and selective for S1PR1. To date, our preliminary data indicate that three F-18 radiotracers are promise for S1PR1 imaging, two of them are F-18 labeled using different procedures and are anticipated to have different pathway compared to [11C]CS1P1. Therefore, in this renewal phase, we will leverage our recent experience with [11C]CS1P1 and develop and transfer an 18F-labeled S1PR1 tracer for clinical investigation. We propose two specific aims: 1) Identify and transfer the most promising 18F-labeled S1PR1 tracer into human investigations. 2) Implement PET imaging human studies in healthy controls and MS patients. When the completion of this application, a clinical suitable S1PR1 18F-radiotracer will be identified and ready to implement for MS and other inflammatory diseases.