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在体评价 alpha7 烟碱型乙酰胆碱受体激动剂 [11C]A-582941 和 [11C]A-844606 在小鼠和清醒猴中的活性。

In vivo evaluation of alpha7 nicotinic acetylcholine receptor agonists [11C]A-582941 and [11C]A-844606 in mice and conscious monkeys.

机构信息

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

出版信息

PLoS One. 2010 Feb 1;5(2):e8961. doi: 10.1371/journal.pone.0008961.

DOI:10.1371/journal.pone.0008961
PMID:20126539
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2813863/
Abstract

BACKGROUND

The alpha7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. The goal of this study was to evaluate the two carbon-11-labeled alpha7 nAChR agonists [(11)C]A-582941 and [(11)C]A-844606 for their potential as novel positron emission tomography (PET) tracers.

METHODOLOGY/PRINCIPAL FINDINGS: The two tracers were synthesized by methylation of the corresponding desmethyl precursors using [(11)C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective alpha7 nAChR agonist (SSR180711). Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [(11)C]A-582941 and [(11)C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [(11)C]A-582941 and [(11)C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711.

CONCLUSIONS/SIGNIFICANCE: A nonhuman primate study suggests that [(11)C]A-582941 and [(11)C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain.

摘要

背景

α7 型烟碱型乙酰胆碱受体（nAChRs）在精神神经疾病（如精神分裂症和阿尔茨海默病）的病理生理学中发挥着重要作用。本研究的目的是评估两种碳-11 标记的 α7 nAChR 激动剂[(11)C]A-582941 和[(11)C]A-844606 作为新型正电子发射断层扫描（PET）示踪剂的潜力。

方法/主要发现：通过使用[(11)C]甲基三氟甲磺酸对相应的去甲基前体进行甲基化，合成了这两种示踪剂。通过在每种示踪剂与载体或过量的选择性α7 nAChR 激动剂（SSR180711）一起注射，来确定在小鼠中的受体阻断作用。使用放射性 HPLC 研究代谢稳定性。在清醒的猴子中进行了有/无 SSR180711 处理的动态 PET 扫描。[(11)C]A-582941 和[(11)C]A-844606 在小鼠脑中表现出高摄取。在脑中，大多数放射性化合物以未改变的形式被检测到。然而，在小鼠脑中，两种化合物都没有表现出明显的区域选择性和选择性受体阻断。另一方面，在清醒猴子的脑中，[(11)C]A-582941 和[(11)C]A-844606 的总分布容积在海马体和丘脑较高，但在小脑较低，且经 SSR180711 预处理后降低。

结论/意义：非人类灵长类动物研究表明，[(11)C]A-582941 和[(11)C]A-844606 可能成为人类大脑中成像 α7 nAChR 的潜在 PET 配体。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba58/2813863/0466605a49e5/pone.0008961.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba58/2813863/a84c8d1189eb/pone.0008961.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba58/2813863/e382070a0199/pone.0008961.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba58/2813863/adb1c6449ad7/pone.0008961.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba58/2813863/67e8b5494ebc/pone.0008961.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba58/2813863/0466605a49e5/pone.0008961.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba58/2813863/a84c8d1189eb/pone.0008961.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba58/2813863/e382070a0199/pone.0008961.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba58/2813863/adb1c6449ad7/pone.0008961.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba58/2813863/67e8b5494ebc/pone.0008961.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba58/2813863/0466605a49e5/pone.0008961.g005.jpg

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