18F‐Labeled benzylpiperazine derivatives as highly selective ligands for imaging σ1 receptor with positron emission tomography. (11th July 2019) - Ye, Jiajun
Abstract : 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 ( K i (σ1 ) = 0.31‐4.19 nM) and high subtype selectivity ( K i (σ2 )/ K i (σ1 ) = 50‐2448). The fluoroethoxy analogues also exhibited high selectivity toward the vesicular acetylcholine transporter ( K i (VAChT)/ K i (σ1 ) = 99‐18252). The corresponding radiotracers [ 18 F]13, [ 18 F]14, and [ 18 F]16 with high selectivity ( K i (σ2 )/ K i (σ1 ) > 100, K i (VAChT)/ K i (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. Abstract : We report a new series of benzylpiperazine derivatives with low nanomolar affinity for σ1 receptors and high subtype selectivity as well as high selectivity toward the vesicular acetylcholine transporter. [ 18 F]16 displayed high brain uptake, high brain‐to‐blood ratios, high specificity, and good metabolic stability in vivo . However, its kinetics in the mouse brain appeared to be very slow. Future effort should be directed toward structural modifications of [ 18 F]16 to explore new potential radiotracers with suitable kinetics for imaging σ1 receptors.