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

PET 1-磷酸鞘氨醇受体 1 (S1P1) 放射性示踪剂用于多发性硬化症的炎症反应

基本信息

批准号：
10660824
负责人：
Tammie Lee Smith Benzinger
金额：
$ 64.09万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660824
关键词：
Acute Address Adverse event Affect Amines Autoimmune Autoimmune Responses Autopsy Biodistribution Biological Markers Brain Brain imaging Cells Central Nervous System Cervical spine Chemistry Clinical Clinical Trials Custom Cyclic GMP Cyclotrons Data Dedications Demyelinations Diagnosis Direct Costs Disease Dose Drug Kinetics Endothelial Cells Evaluation Experimental Autoimmune Encephalomyelitis FDA approved Facilities and Administrative Costs Fluorine Funding Genetic Transcription Goals High Pressure Liquid Chromatography Human Image Imaging Techniques Immune Immune response In Vitro Inflammation Inflammatory Inflammatory Infiltrate Injections Investigation Kinetics Label Lead Lesion Ligands Liver Lymphocyte Measurement Measures Mediating Methods Modeling Molecular Structure Monitor Multiple Sclerosis Neurodegenerative Disorders Organ Oxides Pathway interactions Patients Phase Plasma Positron-Emission Tomography Procedures Process Radiochemistry Rattus Relapsing-Remitting Multiple Sclerosis Running Safety Sampling Sphingosine-1-Phosphate Receptor Testing Tissues Toxic effect Tracer United States Validation X-Ray Computed Tomography blood-brain barrier crossing clinical investigation cost estimate data acquisition dosimetry experience first-in-human gray matter healthy volunteer human imaging human study human subject imaging agent imaging study in vivo imaging innovation lipophilicity lymph nodes mRNA Expression metabolic abnormality assessment multiple sclerosis patient neuroinflammation nonhuman primate protein expression radiation absorbed dose radiotracer repaired response safe patient scale up screening trafficking uptake white matter young adult

Acute Address Adverse event Affect Amines Autoimmune Autoimmune Responses Autopsy Biodistribution Biological Markers Brain Brain imaging Cells Central Nervous System Cervical spine Chemistry Clinical Clinical Trials Custom Cyclic GMP Cyclotrons Data Dedications Demyelinations Diagnosis Direct Costs Disease Dose Drug Kinetics Endothelial Cells Evaluation Experimental Autoimmune Encephalomyelitis FDA approved Facilities and Administrative Costs Fluorine Funding Genetic Transcription Goals High Pressure Liquid Chromatography Human Image Imaging Techniques Immune Immune response In Vitro Inflammation Inflammatory Inflammatory Infiltrate Injections Investigation Kinetics Label Lead Lesion Ligands Liver Lymphocyte Measurement Measures Mediating Methods Modeling Molecular Structure Monitor Multiple Sclerosis Neurodegenerative Disorders Organ Oxides Pathway interactions Patients Phase Plasma Positron-Emission Tomography Procedures Process Radiochemistry Rattus Relapsing-Remitting Multiple Sclerosis Running Safety Sampling Sphingosine-1-Phosphate Receptor Testing Tissues Toxic effect Tracer United States Validation X-Ray Computed Tomography blood-brain barrier crossing clinical investigation cost estimate data acquisition dosimetry experience first-in-human gray matter healthy volunteer human imaging human study human subject imaging agent imaging study in vivo imaging innovation lipophilicity lymph nodes mRNA Expression metabolic abnormality assessment multiple sclerosis patient neuroinflammation nonhuman primate protein expression radiation absorbed dose radiotracer repaired response safe patient scale up screening trafficking uptake white matter young adult

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项目摘要

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.

A.项目摘要/摘要该更新R01应用的目的是确定一个标记的辐射架，以定量测量多发性硬化症患者（MS）患者中的鞘氨氨酸1-磷酸受体1（S1PR1）表达。 MS是关联的淋巴细胞介导的自身免疫反应最终导致重复的脱髓鞘循环和维修。 S1PR1在淋巴细胞和内皮细胞上广泛表达，并参与其中自身免疫性炎症过程通过调节大脑中的免疫细胞运输。目前，四个S1P 调节器Fingolimod，Siponimod，Ozanimod和Ponesimod已被FDA批准用于治疗MS，但 MS中S1PR1的病理生理机制仍然不太了解。正电子发射断层扫描（PET）研究MS和其他疾病中的S1PR1功能受到缺乏临床合适的限制 radiotracer。为了满足这种紧急临床需求，我们的团队成功转移了[11C] CS1P1，A C-11 S1PR1 放射性示例进行临床研究。我们的人类研究数据证实肝脏是辐射的关键器官吸收剂量，[11C] CS1P1对于接受高达740 MBQ（20 MCI）的患者是安全的。我们的概念证明的大脑研究表明，灰质中[11C] CS1P1的吸收比白质相比，一致在正常的人脑中具有S1PR1 mRNA的表达。在MS患者中，我们观察到[11C] CS1P1增加在脑病变和正常出现的白质（WM）中的吸收。这些结果与在MS中，脑损伤和正常出现的炎症性浸润的现有证据。一起，我们的数据表明，S1PR1蛋白表达的PET测量可以提供一种独特的方法来检测 MS患者的神经炎症和反应。我们对人血浆的初始放射代谢物分析在注射[11C] CS1P1后发现了亲脂性放射代谢物，并引起了最初的关注。但是，我们最近确认了放射性代谢物的分子结构和大鼠脑的放射代谢物分析和血浆注射后的放射性示踪剂和宠物脑研究的F-18标记为放射性碱棒的研究证明辐射代谢物不会进入大脑。此外，我们的团队合成了〜120 新的结构上多样化的S1PR1配体，其中约30种具有高效（IC50 <20 nm），并且选择性 S1PR1。迄今为止，我们的初步数据表明，三个F-18辐射示例是S1PR1成像的承诺，两个其中其中的F-18使用不同的步骤标记，并且预计与 [11C] CS1P1。因此，在这个续签阶段，我们将利用[11C] CS1P1和开发和转移18F标记的S1PR1示踪剂进行临床研究。我们提出了两个具体目标：1）识别并将最有希望的18F标记的S1PR1示踪剂转移到人类研究中。 2）实施宠物成像健康对照和MS患者的人类研究。完成此应用程序时，临床将确定合适的S1PR1 18F-Radiotracer，并准备为MS和其他炎症性疾病实施。