[11C]AZ10419369:: A selective 5-HT1B receptor radioligand suitable for positron emission tomography (PET).: Characterization in the primate brain
[11C]AZ10419369:: A selective 5-HT1B receptor radioligand suitable for positron emission tomography (PET).: Characterization in the primate brain
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DOI：
10.1016/j.neuroimage.2008.02.063
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发表时间：
2008-07-01
期刊：
影响因子：
5.7
通讯作者：
Halldin, Christer
中科院分区：
文献类型：
--
作者：
Pierson, M. Edward;Andersson, Jan;Halldin, Christer
5-羟色胺（1B）受体与多种精神疾病有关，是治疗抑郁症的潜在药理靶点。在这里，我们报道了一种新的PET放射配体[(11)C]AZ10419369（5-甲基-8-（4-甲基-哌嗪-1-基）-4-氧-4- h -铬-2-羧酸（4-morpholin-4-基-苯基）-酰胺）的合成，用于在猕猴和人类受试者的大脑中观察5-HT1B受体。[(11)C]AZ10419369是由(8-（1-哌嗪基）5-甲基铬-2-烯-4- 1- 2-（4-啉苯基）甲酰胺以碳-11甲基三氟酸酯为原料n-甲基化而成。用PET对两只猕猴和两名人类受试者进行了初步研究，并对AZ10419369的脑区域摄取模式进行了表征。此外，制备了氚标记形式的AZ10419369，用于猕猴脑组织切片的体外放射自显影研究。[(11)C]AZ10419369的放射化学纯度为bb1099%，比放射性为bb13600ci / mmol。静脉注射[(11)C]AZ10419369后，7.5 min后脑内出现3-4%。人类和猕猴的大脑放射性区域分布相似，显示枕叶皮层和基底神经节的放射性吸收最高，这与使用[(3)H]AZ10419369进行的放射自显影研究一致。摄取在颞叶和额叶皮质区是中等的，在丘脑较低，在小脑最低。在用选择性5-HT（1B）受体拮抗剂AR-A000002预处理的猕猴中，结合以剂量依赖性的方式减少，与5-HT（1B）受体的特异性结合一致。这些数据支持[11C] AZ10419369作为标记灵长类动物大脑中5-HT（1B）受体的合适放射配体。这种放射性配体可能在未来的研究中有用，评估药物诱导的受体占用和测量精神疾病患者大脑5-HT1B受体水平。(C) 2008年Elsevier Inc.出版
The 5-HT(1B) receptor has been implicated in several psychiatric disorders and is a potential pharmacological target in the treatment of depression. Here we report the synthesis of a novel PET radioligand, [(11)C]AZ10419369 (5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide), for in vivo visualization of 5-HT1B receptors in the brains of macaques and humans subjects. [(11)C]AZ10419369 was prepared by N-methylation of (8-(1-piperazinyl)5- methylchrom-2-en-4-one-2-(4-morpholinophenyl) carboxamide, using carbon-11 methyl triflate. Regional brain uptake patterns of [(11)C]AZ10419369 were characterized by PET measurements in two macaques and a preliminary study in two human subjects. In addition, AZ10419369 was prepared in tritium labeled form for in vitro autoradiography studies in macaque brain tissue sections. The radiochemical purity of [(11)C]AZ10419369 was >99% and specific radioactivity was >3600 Ci/ mmol. After iv injection of [(11)C]AZ10419369, 3-4% was in brain after 7.5 min. The regional brain distribution of radioactivity was similar in humans and macaques showing the highest uptake of radioactivity in the occipital cortex and the basal ganglia, in accord with autoradiographic studies performed using [(3)H]AZ10419369. Uptake was moderate in the temporal and frontal cortical regions, lower in the thalamus and lowest in the cerebellum. In macaques pre-treated with the selective 5-HT(1B) receptor antagonist, AR-A000002, binding was reduced in a dose-dependent manner, consistent with specific binding to 5-HT(1B) receptors. These data support [11C] AZ10419369 as a suitable radioligand for labeling 5-HT(1B) receptors in the primate brain. This radioligand may be useful in future studies evaluating drug-induced receptor occupancy and measurement of brain 5-HT1B receptor levels in patients with psychiatric disorders. (C) 2008 Published by Elsevier Inc.