合成碳-11标记的细胞周期蛋白依赖性激酶1（CK1）抑制剂作为用于阿尔茨海默病成像的新型潜在正电子发射断层显像（PET）放射性示踪剂。
Synthesis of carbon-11-labeled CK1 inhibitors as new potential PET radiotracers for imaging of Alzheimer's disease.
作者信息
Gao Mingzhang, Wang Min, Zheng Qi-Huang
机构信息
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 1345 West 16th Street, Room 202, Indianapolis, IN 46202, USA.
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 1345 West 16th Street, Room 202, Indianapolis, IN 46202, USA.
出版信息
Bioorg Med Chem Lett. 2018 Jul 15;28(13):2234-2238. doi: 10.1016/j.bmcl.2018.05.053. Epub 2018 May 29.
The reference standards methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate (5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-3-methoxybenzamide (5c), and their corresponding desmethylated precursors 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoic acid (6a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-3-hydroxybenzamide (6b), were synthesized from 5-amino-2,2-difluoro-1,3-benzodioxole and 3-substituted benzoic acids in 5 and 6 steps with 33% and 11%, 30% and 7% overall chemical yield, respectively. Carbon-11-labeled casein kinase 1 (CK1) inhibitors, [C]methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate ([C]5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-3-[C]methoxybenzamide ([C]5c), were prepared from their O-desmethylated precursor 6a or 6b with [C]CHOTf through O-[C]methylation and isolated by HPLC combined with SPE in 40-45% radiochemical yield, based on [C]CO and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (MA) at EOB was 370-740 GBq/μmol with a total synthesis time of ∼40-min from EOB.
参考标准品3-((2,2-二氟-5H-[1,3]二氧杂环戊烯并[4',5':4,5]苯并[1,2-d]咪唑-6-基)氨基甲酰基)苯甲酸甲酯(5a)和N-(2,2-二氟-5H-[1,3]二氧杂环戊烯并[4',5':4,5]苯并[1,2-d]咪唑-6-基)-3-甲氧基苯甲酰胺(5c)，以及它们相应的去甲基化前体3-((2,2-二氟-5H-[1,3]二氧杂环戊烯并[4',5':4,5]苯并[1,2-d]咪唑-6-基)氨基甲酰基)苯甲酸(6a)和N-(2,2-二氟-5H-[1,3]二氧杂环戊烯并[4',5':4,5]苯并[1,2-d]咪唑-6-基)-3-羟基苯甲酰胺(6b)，由5-氨基-2,2-二氟-1,3-苯并二氧戊环和3-取代苯甲酸经5步和6步合成，总化学产率分别为33%和11%、30%和7%。碳-11标记的酪蛋白激酶1(CK1)抑制剂，[碳-11]3-((2,2-二氟-5H-[1,3]二氧杂环戊烯并[4',5':4,5]苯并[1,2-d]咪唑-6-基)氨基甲酰基)苯甲酸甲酯([碳-11]5a)和N-(2,2-二氟-5H-[1,3]二氧杂环戊烯并[4',5':4,5]苯并[1,2-d]咪唑-6-基)-3-[碳-11]甲氧基苯甲酰胺([碳-11]5c)，由它们的O-去甲基化前体6a或6b与[碳-11]CHOTf通过O-[碳-11]甲基化制备，并通过HPLC结合SPE分离，基于[碳-11]CO且衰变校正至轰击结束(EOB)时的放射化学产率为40 - 45%。放射化学纯度>99%，EOB时的摩尔活度(MA)为370 - 740 GBq/μmol，从EOB开始的总合成时间约为40分钟。
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