¹⁸F‐Labeled benzylpiperazine derivatives as highly selective ligands for imaging σ₁ receptor with positron emission tomography

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 (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 [18F]13, [18F]14, and [18F]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, [18F]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, [18F]16 can serve as a lead compound for further structural modifications to explore new potential radiotracers for σ1 receptors.

In vitroandin vivosigma 1 receptor imaging studies in different disease states

“…Among them are a new series of benzylpiperazine derivatives, which were reported as selective σ1R ligands with high affinity (K i σ 1 = 0.31-4.19 nM) and high subtype selectivity (K i σ 2 /σ 1 = 50-2448). 234 Three of the fluoroethoxy analogs also exhibited high selectivity toward the vesicular acetylcholine transporter, VAChT (K i = 99-18 252), and were chosen for radiolabeling. Radioligands [ 18 F]2, [ 18 F]3, and [ 18 F]4 displayed high initial brain uptake in mice (8.37-11.48% ID per g at 2 min), Fig.…”

Editorial for the special Issue “Jörg Steinbach”

“…Moreover, the development of cell and animal models for a detailed pharmacological radiotracer characterization of, eg, 11 C‐labeled azadipeptides, 18 F‐labeled benzylpiperazines or a cyclic uPA‐derived peptide for the urokinase‐type plasminogen activator receptor follows consistently.…”