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1-(4-[18F]Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine: A Novel Suitable Radioligand with Low Lipophilicity for Imaging σ1 Receptors in the Brain
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-08 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01723
Yingfang He 1 , Fang Xie 1 , Jiajun Ye 1 , Winnie Deuther-Conrad 2 , Bixiao Cui 3 , Liang Wang 1 , Jie Lu 1 , Jörg Steinbach 2 , Peter Brust 2 , Yiyun Huang 4 , Jie Lu 3 , Hongmei Jia 1
Affiliation  

We have designed and synthesized novel piperazine compounds with low lipophilicity as σ1 receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine (10) possessed a low nanomolar σ1 receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ2 receptors (52-fold), and adenosine A2A, adrenergic α2, cannabinoid CB1, dopamine D1, D2L, γ-aminobutyric acid A (GABAA), NMDA, melatonin MT1, MT2, and serotonin 5-HT1 receptors. The corresponding radiotracer [18F]10 demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice. Pretreatment with the selective σ1 receptor agonist SA4503 significantly reduced the level of accumulation of the radiotracer in the brain. No radiometabolite of [18F]10 was observed to enter the brain. Positron emission tomography and magnetic resonance imaging confirmed suitable kinetics and a high specific binding of [18F]10 to σ1 receptors in rat brain. Ex vivo autoradiography showed a reduced level of binding of [18F]10 in the cortex and hippocampus of the senescence-accelerated prone (SAMP8) compared to that of the senescence-accelerated resistant (SAMR1) mice, indicating the potential dysfunction of σ1 receptors in Alzheimer’s disease.

中文翻译:


1-(4-[18F]氟苄基)-4-[(四氢呋喃-2-基)甲基]哌嗪:一种新型的低亲脂性放射性配体,适用于脑内 σ1 受体成像



我们设计并合成了新型低亲脂性哌嗪化合物作为σ 1受体配体。 1-(4-氟苄基)-4-[(四氢呋喃-2-基)甲基]哌嗪 ( 10 ) 具有低纳摩尔 σ 1受体亲和力和对囊泡乙酰胆碱转运蛋白的高选择性(>2000 倍),σ 2受体(52 倍)和腺苷 A 2A 、肾上腺素能 α 2 、大麻素 CB 1 、多巴胺 D 1 、D 2L 、γ-氨基丁酸 A (GABA A )、NMDA、褪黑激素 MT 1 、MT 2和血清素 5- HT 1受体。相应的放射性示踪剂[ 18 F] 10在小鼠生物分布研究中表现出高脑摄取率和极高的脑血比。使用选择性 σ 1受体激动剂 SA4503 进行预处理可显着降低大脑中放射性示踪剂的积累水平。没有观察到[ 18 F] 10的放射性代谢物进入大脑。正电子发射断层扫描和磁共振成像证实了大鼠脑中[ 18 F] 10与σ 1受体的合适动力学和高特异性结合。离体放射自显影显示,与衰老加速抗性 (SAMR1) 小鼠相比,衰老加速易感小鼠 (SAMP8) 的皮质和海马中 [ 18 F] 10的结合水平降低,表明 σ 1的潜在功能障碍阿尔茨海默病的受体。
更新日期:2017-05-08
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