| Summary: | σ<sub>1</sub> receptors play a crucial role in various neurological and neurodegenerative diseases including pain, psychosis, Alzheimer’s disease, and depression. Spirocyclic piperidines represent a promising class of potent σ<sub>1</sub> receptor ligands. The relationship between structural modifications and σ<sub>1</sub> receptor affinity and selectivity over σ<sub>2</sub> receptors led to the 2-fluoroethyl derivative fluspidine (<b>2</b>, <i>K</i><sub>i</sub> = 0.59 nM). Enantiomerically pure (<i>S</i>)-configured fluspidine ((<i>S</i>)-<b>2</b>) was prepared by the enantioselective reduction of the α,β-unsaturated ester <b>23</b> with NaBH<sub>4</sub> and the enantiomerically pure co-catalyst (<i>S</i>,<i>S</i>)-<b>24</b>. The pharmacokinetic properties of both fluspidine enantiomers (<i>R</i>)-<b>2</b> and (<i>S</i>)-<b>2</b> were analyzed in vitro. Molecular dynamics simulations revealed very similar interactions of both fluspidine enantiomers with the σ<sub>1</sub> receptor protein, with a strong ionic interaction between the protonated amino moiety of the piperidine ring and the COO<sup>-</sup> moiety of glutamate 172. The <sup>18</sup>F-labeled radiotracers (<i>S</i>)-[<sup>18</sup>F]<b>2</b> and (<i>R</i>)-[<sup>18</sup>F]<b>2</b> were synthesized in automated syntheses using a TRACERlab FX FN synthesis module. High radiochemical yields and radiochemical purity were achieved. Radiometabolites were not found in the brains of mice, piglets, and rhesus monkeys. While both enantiomers revealed similar initial brain uptake, the slow washout of (<i>R</i>)-[<sup>18</sup>F]<b>2</b> indicated a kind of irreversible binding. In the first clinical trial, (<i>S</i>)-[<sup>18</sup>F]<b>2</b> was used to visualize σ<sub>1</sub> receptors in the brains of patients with major depressive disorder (MDD). This study revealed an increased density of σ<sub>1</sub> receptors in cortico-striato-(para)limbic brain regions of MDD patients. The increased density of σ<sub>1</sub> receptors correlated with the severity of the depressive symptoms. In an occupancy study with the PET tracer (<i>S</i>)-[<sup>18</sup>F]<b>2</b>, the selective binding of pridopidine at σ<sub>1</sub> receptors in the brain of healthy volunteers and HD patients was shown.
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