We report the design, synthesis, and evaluation of a new series of benzylpiperazine derivatives as selective σ1 receptor ligands. All seven ligands possessed low nanomolar affinity for σ1 receptors (Ki (σ1 ) = 0.31-4.19 nM) and high subtype selectivity (Ki (σ2 )/Ki (σ1 ) = 50-2448). The fluoroethoxy analogues also exhibited high selectivity toward the vesicular acetylcholine transporter (Ki (VAChT)/Ki (σ1 ) = 99-18252). The corresponding radiotracers [18 F]13, [18 F]14, and [18 F]16 with high selectivity (Ki (σ2 )/Ki (σ1 ) > 100, Ki (VAChT)/Ki (σ1 ) > 1000) were prepared in 42% to 55% radiochemical yields (corrected for decay), greater than 99% radiochemical purity (RCP), and molar activity of about 120 GBq/μmol at the end of synthesis (EOS). All three radiotracers showed high initial brain uptake in mouse (8.37-11.48% ID/g at 2 min), which was not affected by pretreatment with cyclosporine A, suggesting that they are not substrates for permeability-glycoprotein (P-gp). Pretreatment with SA4503 or haloperidol resulted in significantly reduced brain uptake (35%-62% decrease at 30 min). In particular, [18 F]16 displayed high brain-to-blood ratios and high in vivo metabolic stability. Although it may not be an optimal neuroimaging agent because of its slow kinetics in the mouse brain, [18 F]16 can serve as a lead compound for further structural modifications to explore new potential radiotracers for σ1 receptors.
Keywords: benzylpiperazine derivatives; fluorine-18; positron emission tomography; sigma-1 receptor.
© 2019 John Wiley & Sons, Ltd.