Development of Radiotracers for Imaging of Sigma1-Receptors in the Human Brain

开发用于人脑 Sigma1 受体成像的放射性示踪剂

• 批准号: 233201168
• 负责人: Professor Dr. Osama Sabri
• 金额: --
• 依托单位: Institut für Pharmazeutische und Medizinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/233201168?language=en
• 关键词: Development; Radiotracers; Imaging; Sigma1; Receptors

Sigma1 receptors are a potential target for the treatment of depression and other brain diseases, and there is strong evidence that modulation of the serotonergic system by sigma1 receptor ligands may provide a new alternative for treatment-resistant depressed patients. This project aims at the development of a 18F-labelled radiotracer for clinical imaging of sigma1 receptors in brain with positron emission tomography (PET). No such radiotracer is currently available for human use. During the first two funding periods of this project a series of sigma1 receptor selective compounds has been developed and their affinity, selectivity and their metabolism in vitro as well as stability, lipophilicity, in vivo metabolism, biodistribution, brain uptake and imaging properties of their 18F-labelled equivalents have been investigated. It has been shown that the spirocyclic benzofuran-based radioligand [18F]fluspidine offers potential for neuroimaging and quantitation of sigma1 receptors with PET. Chiral separation of the racemic fluspidine and precursor compound has been successfully achieved and the two radiolabelled enantiomers of fluspidine have been investigated in first preclinical studies. Based on these data the (S)-configured fluspidine derivative is chosen for a proof-of-concept study in humans. It is the initial objective of this project to assess the availability of sigma1 receptors in patients with major depressive disorder compared with age- and gender-matched healthy controls by using (S)-[18F]fluspidine.

Sigma 1受体是治疗抑郁症和其他脑部疾病的潜在靶点，并且有强有力的证据表明，Sigma 1受体配体对多巴胺能系统的调节可能为治疗难治性抑郁症患者提供新的选择。本项目旨在开发18F标记的放射性示踪剂，用于正电子发射断层扫描（PET）脑中sigma 1受体的临床成像。目前没有这种放射性示踪剂可供人类使用。在该项目的前两个资助期内，开发了一系列sigma 1受体选择性化合物，并研究了它们的亲和力、选择性和体外代谢以及稳定性、亲脂性、体内代谢、生物分布、脑摄取和18F标记等效物的成像特性。研究表明，基于螺环苯并呋喃的放射性配体[18 F]氟匹定具有神经成像和PET定量sigma 1受体的潜力。已成功实现外消旋氟斯匹定和前体化合物的手性分离，并在首次临床前研究中研究了氟斯匹定的两种放射性标记对映体。基于这些数据，选择（S）-构型氟斯匹定衍生物用于人体概念验证研究。本项目的最初目的是通过使用（S）-[18F]氟斯匹定评估重度抑郁症患者与年龄和性别匹配的健康对照组相比sigma 1受体的可用性。

项目成果

Synthesis of Substituted 1‐Alkylidenephthalanes via Lithium‐Promoted 5‐exo‐dig Cyclization

通过锂促进的 5âexoâdig 环化合成取代的 1â 亚烷基酞烷

• DOI: 10.1002/ejoc.201800205
• 发表时间: 2018
• 期刊: European Journal of Organic Chemistry
• 影响因子: 2.8
• 作者: Bunse P;Würthwein EU;Wünsch B
• 通讯作者: Wünsch B

Comparison of in Silico, Electrochemical, in Vitro and in Vivo Metabolism of a Homologous Series of (Radio)fluorinated σ1 Receptor Ligands Designed for Positron Emission Tomography

用于正电子发射断层扫描的同源系列（无线电）氟化 Ï1 受体配体的计算机模拟、电化学、体外和体内代谢比较

• DOI: 10.1002/cmdc.201600366
• 发表时间: 2016
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: Wiese C;Große Maestrup E;Galla F;Schepmann D;Hiller A;Fischer S;Ludwig FA;Deuther-Conrad W;Donat CK;Brust P;Büter L;Karst U;Wünsch B
• 通讯作者: Wünsch B

PET Imaging Evaluation of Four σ1 Radiotracers in Nonhuman Primates

• DOI: 10.2967/jnumed.116.188052
• 发表时间: 2017-06-01
• 期刊: JOURNAL OF NUCLEAR MEDICINE
• 影响因子: 9.3
• 作者: Baum, Evan;Cai, Zhengxin;Huang, Yiyun
• 通讯作者: Huang, Yiyun