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

被引：7

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.

引用

页数：4

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