18F-Labeled benzylpiperazine derivatives as highly selective ligands for imaging σ1 receptor with positron emission tomography
18F-Labeled benzylpiperazine derivatives as highly selective ligands for imaging σ1 receptor with positron emission tomography
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18F标记的苄基哌嗪衍生物作为高选择性配体，用于正电子发射断层扫描成像Ï1受体
DOI：
10.1002/jlcr.3738
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发表时间：
2019
影响因子：
1.8
通讯作者：
Jia Hongmei
中科院分区：
文献类型：
--
作者：
Ye Jiajun;Wang Liang;Deuther-Conrad Winnie;Chen Yuanyuan;Zhang Xiaojun;Zhang Jinming;Huang Yiyun;Brust Peter;Jia Hongmei
我们报道了一系列新的苯哌嗪衍生物作为选择性σ1受体配体的设计、合成和评价。7种配体对σ1受体具有低纳摩尔亲和力（Ki(σ1) = 0.31 ~ 4.19 nM）和高亚型选择性(Ki（σ2)/Ki(σ1) = 50 ~ 2448）。氟乙氧基类似物对囊泡型乙酰胆碱转运体也表现出高选择性(Ki（VAChT)/Ki(σ1) = 99‐18252）。相应的放射性示踪剂[18F]13、[18F]14和[18F]16具有高选择性(Ki(σ2)/Ki(σ1) > 100,Ki(VAChT)/Ki(σ1) > 1000)，放射化学产率（校正衰变）为42% ~ 55%，放射化学纯度（RCP）大于99%，合成结束时摩尔活性约为120 GBq/μmol （EOS）。所有三种放射性示踪剂在小鼠中显示出高的初始脑摄取（2分钟时8.37‐11.48% ID/g），不受环孢素A预处理的影响，表明它们不是通透性糖蛋白（P‐gp）的底物。SA4503或氟哌啶醇预处理可显著降低脑摄取（30分钟降低35% - 62%）。特别是，[18F]16显示出高脑血比和高体内代谢稳定性。尽管由于其在小鼠大脑中的缓慢动力学，它可能不是一种最佳的神经显像剂，[18F]16可以作为进一步结构修饰的先导化合物，以探索新的潜在的σ1受体放射性示踪剂。
We report the design, synthesis, and evaluation of a new series of benzylpiperazine derivatives as selective σ1receptor ligands. All seven ligands possessed low nanomolar affinity for σ1receptors (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]16with 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]16displayed high brain‐to‐blood ratios and highinvivometabolic stability. Although it may not be an optimal neuroimaging agent because of its slow kinetics in the mouse brain, [18F]16can serve as a lead compound for further structural modifications to explore new potential radiotracers for σ1receptors.