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

Sigma1受体是治疗抑郁症和其他脑部疾病的潜在靶点，有强有力的证据表明，通过Sigma1受体配体调节血清素能系统可能为治疗抵抗性抑郁症患者提供新的选择。本项目旨在开发一种18f标记的放射性示踪剂，用于使用正电子发射断层扫描（PET）对大脑sigma1受体进行临床成像。目前还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，已经开发了一系列sigma1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，脑摄取和其18f标记等同物的成像特性。研究表明，以螺环苯并呋喃为基础的放射配体[18F]氟平定具有PET神经成像和定量sigma1受体的潜力。已成功地实现了外消旋氟平与前体化合物的手性分离，并在首次临床前研究中对氟平的两种放射性标记对映体进行了研究。根据这些数据，选择(S)配置的氟平定衍生物进行人类概念验证研究。本项目的最初目的是通过使用(S)-[18F]氟平定，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，sigma1受体的可用性。

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.