Synthesis, Characterization, and Metabolism Studies of Fluspidine Enantiomers

The enantiomers of the potent σ 1 ligand fluspidine ( 1 ) were prepared by using chiral preparative HPLC. Synthesis of racemic tosylate 2 and subsequent separation of enantiomers yielded ( R )‐ 2 and ( S )‐ 2 in excellent enantiomeric purities. The fluspidine enantiomers ( R )‐ 1 and ( S )‐ 1 were synthesized from ( R )‐ 2 and ( S )‐ 2 by nucleophilic substitution with tetra‐ n ‐butylammonium fluoride, affording ( R )‐ 1 with 99.6 %  ee and ( S )‐ 1 with 96.4 %  ee . Tosylates ( R )‐ 2 and ( S )‐ 2 can also serve as precursors for the radiosynthesis of enantiomerically pure radiotracers [ 18 F]( R )‐ 1 and [ 18 F]( S )‐ 1 . The absolute configuration of the pure enantiomers was elucidated by comparison of their CD spectra with a calculated CD spectrum of a simplified model compound. In receptor binding studies, both enantiomers displayed very high σ 1 receptor affinity and selectivity against the σ 2 receptor. ( R )‐Fluspidine (( R )‐ 1 ) is the eutomer, with a K i value of 0.57 n M and a eudysmic ratio of 4. Incubation of ( R )‐ 1 and ( S )‐ 1 with rat liver microsomes led to the identification of seven and eight metabolites, respectively. Although the S ‐configured enantiomer formed additional metabolite ( S )‐ 1‐3 , it is metabolically more stable than ( R )‐ 1 .