11C-AC-5216：一种用于灵长类动物大脑外周苯二氮䓬受体的新型正电子发射断层显像（PET）配体。

11C-AC-5216: a novel PET ligand for peripheral benzodiazepine receptors in the primate brain.

作者信息

Zhang Ming-Rong, Kumata Katsushi, Maeda Jun, Yanamoto Kazuhiko, Hatori Akiko, Okada Maki, Higuchi Makoto, Obayashi Shigeru, Suhara Tetsuya, Suzuki Kazutoshi

机构信息

Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.

出版信息

J Nucl Med. 2007 Nov;48(11):1853-61. doi: 10.2967/jnumed.107.043505.

DOI:10.2967/jnumed.107.043505

PMID:17978354

Abstract

UNLABELLED

Developing a PET ligand for imaging of the peripheral benzodiazepine receptor (PBR; Translocator Protein [18 kDa] TSPO) is of great importance for studying its role in glial cells in the injured brain and in neurodegenerative disorders, such as Alzheimer's disease. The aim of this study was to synthesize and evaluate N-benzyl-N-ethyl-2-(7-(11)C-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ((11)C-AC-5216) as a PET ligand for imaging PBR in the primate brain.

METHODS

AC-5216 and its desmethyl precursor (compound 1) were synthesized starting from commercially available compounds. The radiosynthesis of (11)C-AC-5216 was performed through the reaction of compound 1 with (11)C-CH(3)I in the presence of NaH. The in vivo brain regional distribution was determined in mice (dissection) and a monkey (PET).

RESULTS

(11)C-AC-5216 (800-1,230 MBq; n = 25) was obtained with a radiochemical purity of 98% and a specific activity of 85-130 GBq/mumol at the end of synthesis. After injection of (11)C-AC-5216 into mice, a high accumulation of radioactivity was found in the lungs, heart, adrenal glands, and other PBR-rich organs. In the mouse brain, high radioactivity was observed in the olfactory bulb and cerebellum. Radioactivity in these regions was inhibited by nonradioactive AC-5216 or PK11195 but was not decreased by central benzodiazepine receptor-selective flumazenil and Ro15-4513. A PET study of the monkey brain determined that (11)C-AC-5216 had a relatively high uptake in the occipital cortex, a rich PBR-dense area in the primate brain. Pretreatment with nonradioactive AC-5216 and PK11195 reduced the radioactivity of (11)C-AC-5216 in the occipital cortex significantly, suggesting its high specific binding with PBR in the brain. Metabolite analysis demonstrated that (11)C-AC-5216 was stable in vivo in the mouse brain, although it was metabolized in the plasma of mice and the monkey.

CONCLUSION

(11)C-AC-5216 is a promising PET ligand for imaging PBR in rodent and primate brains.

摘要

未标记

开发一种用于外周苯二氮䓬受体（PBR；转位蛋白[18 kDa]，TSPO）成像的正电子发射断层扫描（PET）配体，对于研究其在脑损伤中的神经胶质细胞以及神经退行性疾病（如阿尔茨海默病）中的作用具有重要意义。本研究的目的是合成并评估N-苄基-N-乙基-2-(7-(11)C-甲基-8-氧代-2-苯基-7,8-二氢-9H-嘌呤-9-基)乙酰胺（(11)C-AC-5216）作为一种用于在灵长类动物脑中成像PBR的PET配体。

方法

从市售化合物开始合成AC-5216及其去甲基前体（化合物1）。(11)C-AC-5216的放射性合成是通过化合物1与(11)C-CH(3)I在NaH存在下反应进行的。在小鼠（解剖）和一只猴子（PET）中测定了体内脑区分布。

结果

合成结束时获得了(11)C-AC-5216（800 - 1230 MBq；n = 25），放射化学纯度为98%，比活度为85 - 130 GBq/μmol。将(11)C-AC-5216注射到小鼠体内后，在肺、心脏、肾上腺和其他富含PBR的器官中发现放射性高度蓄积。在小鼠脑中，嗅球和小脑中观察到高放射性。这些区域的放射性被非放射性AC-5216或PK11195抑制，但未被中枢苯二氮䓬受体选择性氟马西尼和Ro15 - 4513降低。对猴子脑的PET研究确定(11)C-AC-5216在枕叶皮质有相对较高的摄取，枕叶皮质是灵长类动物脑中富含PBR的密集区域。用非放射性AC-5216和PK11195预处理可显著降低(11)C-AC-5216在枕叶皮质的放射性，表明其在脑中与PBR有高特异性结合。代谢物分析表明，(11)C-AC-5216在小鼠脑中体内稳定，尽管它在小鼠和猴子的血浆中会被代谢。