Publications Repository - Helmholtz-Zentrum Dresden-Rossendorf

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¹⁸F-Labeled benzylpiperazine derivatives as highly selective ligands for imaging σ1 receptor with positron emission tomography
Ye, J.; Wang, L.; Deuther-Conrad, W.; Chen, Y.; Zhang, X.; Zhang, J.; Huang, Y.; Brust, P.; Jia, H.;
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.
  • Journal of Labelled Compounds and Radiopharmaceuticals 62(2019)8, 425-437
    DOI: 10.1002/jlcr.3738


Publ.-Id: 29524 - Permalink