[¹⁸F]Fluspidine—A PET Tracer for Imaging of σ₁ Receptors in the Central Nervous System

σ₁ 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 σ₁ receptor ligands. The relationship between structural modifications and σ₁ receptor affinity and selectivity over σ₂ receptors led to the 2-fluoroethyl derivative fluspidine (2, K_i = 0.59 nM). Enantiomerically pure (S)-configured fluspidine ((S)-2) was prepared by the enantioselective reduction of the α,β-unsaturated ester 23 with NaBH₄ and the enantiomerically pure co-catalyst (S,S)-24. The pharmacokinetic properties of both fluspidine enantiomers (R)-2 and (S)-2 were analyzed in vitro. Molecular dynamics simulations revealed very similar interactions of both fluspidine enantiomers with the σ₁ receptor protein, with a strong ionic interaction between the protonated amino moiety of the piperidine ring and the COO^- moiety of glutamate 172. The ¹⁸F-labeled radiotracers (S)-[¹⁸F]2 and (R)-[¹⁸F]2 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 (R)-[¹⁸F]2 indicated a kind of irreversible binding. In the first clinical trial, (S)-[¹⁸F]2 was used to visualize σ₁ receptors in the brains of patients with major depressive disorder (MDD). This study revealed an increased density of σ₁ receptors in cortico-striato-(para)limbic brain regions of MDD patients. The increased density of σ₁ receptors correlated with the severity of the depressive symptoms. In an occupancy study with the PET tracer (S)-[¹⁸F]2, the selective binding of pridopidine at σ₁ receptors in the brain of healthy volunteers and HD patients was shown.