Sigma Receptors: Their Role in Disease and as Therapeutic Targets

Frauke Weber, Peter Brust, Erik Laurini, Sabrina Pricl, Bernhard Wünsch

Sylvia B. Smith, Tsung-Ping Su

At first the role of σ1 receptors in various neurological, psychiatric and neurodegenerative disorders is discussed. In the second part, the principle of positron emission tomography (PET ) is described and the known fluorinated PET tracers for labeling of σ1 receptors are presented. The third part focuses on fluoroalkyl substituted spirocyclic PET tracers, which represent the most promising class of fluorinated PET tracers reported so far. The homologous fluoroalkyl derivatives 12-15 show high σ1 affinity (K i = 0.59-1.4 nM) and high selectivity over the σ2 subtype (408-1331-fold). The enantiomers of the fluoroethyl derivative fluspidine 13 were prepared and pharmacologically characterized. Whereas the (S)-configured enantiomer (S)-13 (K i = 2.3 nM) is 4-fold less active than the (R)-enantiomer (R)-13 (K i = 0.57 nM), (S)-13 is metabolically more stable. The interactions of (S)-13 and (R)-13 with the σ1 receptor were analyzed at the molecular level using the 3D homology model. In an automated radiosynthesis [(18)F](S)-13 and [(18)F](R)-13 were prepared by nucleophilic substitution of the tosylates (S)-17 and (R)-17 with K[(18)F]F in high radiochemical yield, high radiochemical purity and short reaction time. Application of both enantiomers [(18)F](S)-13 and [(18)F](R)-13 to mice and piglets led to fast uptake into the brain, but [(18)F](R)-13 did not show washout from the brain indicating a quasi-irreversible binding. Both radiotracers [(18)F](S)-13 and [(18)F](R)-13 were able to label regions in the mouse and piglet brain with high σ1 receptor density. The specific binding of the enantiomeric tracers [(18)F](S)-13 and [(18)F](R)-13 could be replaced by the selective σ1 ligand SA4503.