Synthesis of (R,S)-isoproterenol, an inhibitor of tau aggregation, as an 11C-labeled PET tracer via reductive alkylation of (R,S)-norepinephrine with [2-11C]acetone
Synthesis of (R,S)-isoproterenol, an inhibitor of tau aggregation, as an 11C-labeled PET tracer via reductive alkylation of (R,S)-norepinephrine with [2-11C]acetone
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通过 (R,S)-去甲肾上腺素与 [2-11C]丙酮的还原烷基化合成 (R,S)-异丙肾上腺素（tau 聚集抑制剂）作为 11C 标记的 PET 示踪剂
DOI：
10.1016/j.bmcl.2019.07.005
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发表时间：
2019
影响因子：
2.7
通讯作者：
Suzuki Masaaki
中科院分区：
文献类型：
--
作者：
Ikenuma Hiroshi;Koyama Hiroko;Kajino Naoya;Kimura Yasuyuki;Ogata Aya;Abe Junichiro;Kawasumi Yasuhiro;Kato Takashi;Takashima Akihiko;Ito Kengo;Suzuki Masaaki
(R，S)-异丙肾上腺素抑制与神经元丢失和认知障碍发展相关的有毒颗粒状tau寡聚体的形成，是治疗阿尔茨海默病的有吸引力的候选药物。为了用正电子发射断层扫描技术阐明其在脑内的行为，我们用(R，S)-去甲肾上腺素与[2-11C]丙酮还原烷基化合成了(R，S)-[11C]异丙肾上腺素，再在改进的条件下原位合成，得到衰变校正的放射化学产率为54%。以苯甲酸为还原剂，以苯甲酸为还原剂，在二甲基亚砜/二甲基甲酰胺(60：40V/V)中，100 °C反应10 ，得到(R，S)-[11C]异丙肾上腺素，产率为87%。(R，S)-[11C]异丙肾上腺素的总放射性为2.0 ± 0.2 GBq，衰变校正放化产率为19 ± 2%，化学和放化纯度分别为71%和99%，摩尔活度为10 0 ± 13 GBq/μ(n= 3)。从轰击结束到药物配方的总合成时间为48 min。一项初步的大鼠临床前正电子发射计算机断层扫描研究表明，放射性配基可用于评价(R，S)-异丙肾上腺素在人脑中的渗透性。
(R,S)-Isoproterenol inhibits the formation of toxic granular tau oligomers associated with neuronal loss and development of cognitive disorders, and is an attractive drug candidate for Alzheimer’s disease. To elucidate its behavior in the brain by positron emission tomography, we synthesize (R,S)-[11C]isoproterenol by reductive alkylation of (R,S)-norepinephrine with [2-11C]acetone, which was in turn synthesized in situ under improved conditions afforded a decay-corrected radiochemical yield of 54%. The reductive alkylation using NaBH(OAc)3as reducing agent in the presence of benzoic acid in DMSO/DMF (60:40v/v) at 100 °C for 10 min gave (R,S)-[11C]isoproterenol in an 87% radio-high performance liquid chromatography (HPLC) analytical yield. HPLC separation using a strong cation exchange column, followed by pharmaceutical formulation in the presence ofd/l-tartaric acid, afforded (R,S)-[11C]isoproterenol with a total radioactivity of 2.0 ± 0.2 GBq, a decay-corrected radiochemical yield of 19 ± 2%, chemical and radiochemical purities of 71% and >99%, respectively, and a molar activity of 100 ± 13 GBq/μmol (n= 3). The overall synthesis time from the end of the bombardment to pharmaceutical formulation was 48 min. A preliminary preclinical PET study in a rat demonstrated the potential of the radioligand for the evaluation of the penetration of (R,S)-isoproterenol in human brain.