采用“环内”[¹⁴C]CO固定法合成¹⁴C标记的胆固醇24-羟化酶抑制剂及其药代动力学研究
Synthesis and pharmacokinetic study of a C-labeled cholesterol 24-hydroxylase inhibitor using 'in-loop' [C]CO fixation method.
作者信息
Chen Zhen, Chen Jiahui, Mast Natalia, Rong Jian, Deng Xiaoyun, Shao Tuo, Fu Hualong, Yu Qingzhen, Sun Jiyun, Shao Yihan, Josephson Lee, Collier Thomas Lee, Pikuleva Irina, Liang Steven H
机构信息
Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA.
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
出版信息
Bioorg Med Chem Lett. 2020 May 1;30(9):127068. doi: 10.1016/j.bmcl.2020.127068. Epub 2020 Mar 6.
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 Aβ 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.
胆固醇24-羟化酶，也称为CYP46A1（EC 1.14.13.98），是一种单加氧酶，属于细胞色素P450家族。CYP46A1在大脑中特异性表达，通过产生24S-羟基胆固醇（24-HC）作为主要代谢产物来控制胆固醇的清除。调节CYP46A1活性可能通过改变24-HC的形成来影响Aβ沉积和p- tau积累，这其后可作为阿尔茨海默病的潜在治疗途径。在这项工作中，我们展示了一种用于正电子发射断层扫描的新型胆固醇24-羟化酶抑制剂1的高效合成及初步药代动力学评估。
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