Novel [18F]-Labeled Meta-Bromobenzylguanidine Derivatives: Potential Positron Emission Tomography Imaging Probes for the Norepinephrine Transporter.
Novel [18F]-Labeled Meta-Bromobenzylguanidine Derivatives: Potential Positron Emission Tomography Imaging Probes for the Norepinephrine Transporter.
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DOI：
10.1021/acs.molpharmaceut.1c00429
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发表时间：
2021-09
影响因子：
4.9
通讯作者：
Xiaoyan Li;Shuyu Shi;Hang Zhou;Zuoquan Zhao;Jie Lu
中科院分区：
文献类型：
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作者：
Xiaoyan Li;Shuyu Shi;Hang Zhou;Zuoquan Zhao;Jie Lu
为了开发新型的靶向去甲肾上腺素转运蛋白（NET）的正电子发射断层扫描（PET）探针，合成了一系列间溴苄基胍衍生物。4-氟二乙氧基乙烷-3-溴苄基胍（化合物12）对NET显示出相对较好的亲和力（IC 50 = 1.00 ± 0.04 μM）。通过三步法制备了高放化纯度（>98%）的相应放射性示踪剂18F-12。体外细胞摄取结果表明，18 F-12通过摄取-1机制被表达NET的SK-N-SH细胞特异性摄取。小鼠中的生物分布研究显示，18F-12表现出高心脏摄取（在5分钟p.i.和6.44 ± 0.40% ID/g（在120 min p.i.），肝脏清除更快，吸收的辐射剂量低于[123 I]-标记的间碘苄胍（[123 I]MIBG）。小动物PET成像证实了18F-12的高心脏-背景比和大鼠NET特异性的摄取-1机制，表明其作为心脏交感神经成像的有前途的PET放射性示踪剂的潜力。
To develop novel norepinephrine transporter (NET)-targeting positron emission tomography (PET) probes with optimal pharmacokinetic properties, a series of meta-bromobenzylguanidine derivatives was synthesized. 4-Fluorodiethoxyethane-3-bromobenzylguanidine (compound 12) showed relatively good affinity for the NET (IC50 = 1.00 ± 0.04 μM). The corresponding radiotracer 18F-12 was prepared in high radiochemical purity (>98%) via a three-step method. The in vitro cellular uptake results demonstrated that 18F-12 was specifically taken up by NET-expressing SK-N-SH cells by the uptake-1 mechanism. Biodistribution studies in mice showed that 18F-12 exhibited high cardiac uptake (10.45 ± 0.66 %ID/g at 5 min p.i. and 6.44 ± 0.40 %ID/g at 120 min p.i.), faster liver clearance, and a lower dose of absorbed radiation than [123I]-labeled meta-iodobenzylguanidine ([123I]MIBG). Small animal PET imaging confirmed the high heart-to-background ratio of 18F-12 and the uptake-1 mechanism specific for the NET in rats, indicating its potential as a promising PET radiotracer for cardiac sympathetic nerve imaging.