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

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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.