Synthesis and pharmacokinetic study of a 11C-labeled cholesterol 24-hydroxylase inhibitor using 'in-loop' [11C]CO2 fixation method

被引：6
|
作者：
Chen, Zhen [1 ,2 ]
Chen, Jiahui [1 ,2 ]
Mast, Natalia [3 ]
Rong, Jian [1 ,2 ]
Deng, Xiaoyun [1 ,2 ]
Shao, Tuo [1 ,2 ]
Fu, Hualong [1 ,2 ]
Yu, Qingzhen [1 ,2 ]
Sun, Jiyun [1 ,2 ]
Shao, Yihan [4 ]
Josephson, Lee [1 ,2 ]
Collier, Thomas Lee [1 ,2 ]
Pikuleva, Irina [3 ]
Liang, Steven H. [1 ,2 ]
机构：
[1] Harvard Med Sch, Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA
[2] Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA
[3] Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA
[4] Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2020年 / 30卷 / 09期
关键词：
Cholesterol; 24-hydroxylase; CYP46A1; Alzheimer's disease; Positron emission tomography; C-11]CO2 fixation; CYTOCHROME-P450; 46A1; CYP46A1; INHIBITION; ENZYME; BINDING; GENE;
D O I：
10.1016/j.bmcl.2020.127068
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Cholesterol 24-hydroxylase, also known as CYP46A1 (EC 1.14.13.98), is a monooxygenase and a member of the cytochrome P450 family. CYP46A1 is specifically expressed in the brain where it controls cholesterol elimination by producing 24S-hydroxylcholesterol (24-HC) as the major metabolite. Modulation of CYP46A1 activity may affect A beta deposition and p-tau accumulation by changing 24-HC formation, which thereafter serves as potential therapeutic pathway for Alzheimer's disease. In this work, we showcase the efficient synthesis and preliminary pharmacokinetic evaluation of a novel cholesterol 24-hydroxylase inhibitor 1 for use in positron emission tomography.
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页数：4
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