Synthesis and preliminary evaluation of benzylaminoimidazoline derivatives as novel norepinephrine transporter ligands
Synthesis and preliminary evaluation of benzylaminoimidazoline derivatives as novel norepinephrine transporter ligands
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DOI：
10.1111/cbdd.14282
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发表时间：
2023-06-16
影响因子：
3
通讯作者：
Lu，Jie
中科院分区：
文献类型：
--
作者：
Zhou，Hang;Yao，Jingjing;Lu，Jie
合成了一系列苄氨基咪唑啉衍生物，并评价了其对去甲肾上腺素转运蛋白（NET）的靶向作用。其中，N-（3-碘苄基）-4，5-二氢-1H-咪唑-2-胺（化合物9）对NET的亲和力最高（IC 50 = 5.65 ± 0.97 μM）。相应的放射性示踪剂[125 I] 9通过铜介导的放射性碘化进一步制备，并在体外和体内进行评价。细胞摄取结果表明，[125 I] 9被表达NET的SK‐N‐SH细胞系特异性摄取。生物分布研究表明，[125 I] 9在心脏中积累（5.54 ± 1.24%ID/g，5 min p.i.和0.79 ± 0.08% ID/g（在p.i.和肾上腺（14.83 ± 3.47%ID/g，p.i.和3.87 ± 0.24% ID/g（在2 h p.i.）。预先注射去甲丙咪嗪（地昔帕明）可明显抑制心脏和肾上腺的摄取。这些结果表明，苄基氨基咪唑啉衍生物保留了对NET的亲和性，为进一步研究提供了构效关系数据。
A series of benzylaminoimidazoline derivatives was synthesized and evaluated for norepinephrine transporter (NET) targeting. Among them, N‐(3‐iodobenzyl)‐4,5‐dihydro‐1H‐imidazol‐2‐amine (Compound9) displayed the highest affinity for NET (IC50= 5.65 ± 0.97 μM). The corresponding radiotracer[125I]9was further prepared by copper‐mediated radioiodination and evaluated both in vitro and in vivo. The cellular uptake results suggested that[125I]9was specifically taken up by the NET‐expressing SK‐N‐SH cell line. Biodistribution studies showed that[125I]9accumulated in the heart (5.54 ± 1.24 %ID/g at 5 min p.i. and 0.79 ± 0.08 %ID/g at 2 h p.i.) and adrenal gland (14.83 ± 3.47 %ID/g at 5 min p.i. and 3.87 ± 0.24 %ID/g at 2 h p.i.). The uptake in the heart and adrenal gland could be significantly inhibited by preinjection of desipramine (DMI). These results indicated that the benzylaminoimidazoline derivatives retained affinity for NET, which could provide structure–activity relationship data for further studies.