A hyperpolarized choline molecular probe for monitoring acetylcholine synthesis
A hyperpolarized choline molecular probe for monitoring acetylcholine synthesis
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DOI：
10.1002/cmmi.418
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发表时间：
2011-05-01
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通讯作者：
Katz-Brull, Rachel
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文献类型：
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作者：
Allouche-Arnon, Hyla;Gamliel, Ayelet;Katz-Brull, Rachel
胆碱作为报告分子的体内磁共振研究已有近三十年的历史。在临床前模型、体外模型、体内模型和患者体内，已经观察到胆碱代谢产物(主要是磷酸化形式)在恶性肿瘤中的积累。结合胆碱代谢产物信号出现在脑的H-1-MRS中，其相对强度在各种情况下都被用作诊断因子。体内使用的自旋超极化方法的出现引起了人们对跟踪胆碱在大脑中转化为乙酰胆碱的生理代谢能力的兴趣。在这里，我们提出了一种稳定同位素标记的胆碱类似物，[1，1，2，2-D-4，2-C-13]，它适合于这一目的。在这个模拟中，在DNP超极化之后，C-13位置在液体状态下表现出24%的极化。这个核在11.8T和25℃时也显示出长T-1(35 S)，这是超极化研究的先决条件。这个C-13位的化学位移使胆碱和乙酰胆碱相互区别，并有别于其他水溶性胆碱代谢物，即磷胆碱和甜菜碱。使用乙酰基转移酶的酶学研究表明，在热平衡条件下，在超极化状态下合成了氚-乙酰胆碱形式。综合模型的分析表明，形成的超极化[1，1，2，2-D-4，2-C-13]乙酰胆碱在14.1T和37℃下的T-1为34 S。我们得出结论：[1，1，2，2-D-4，2-C-13]胆碱是一种很有前途的新型超极化代谢分子探针，并讨论了其在体内可能使用的相关因素。版权所有(C)2010 John Wiley&Sons，Ltd.。支持信息可在本文的在线版本中找到。
Choline as a reporter molecule has been investigated by in vivo magnetic resonance for almost three decades. Accumulation of choline metabolites (mainly the phosphorylated forms) had been observed in malignancy in preclinical models, ex-vivo, in vivo and in patients. The combined choline metabolite signal appears in H-1-MRS of the brain and its relative intensity had been used as a diagnostic factor in various conditions. The advent of spin hyperpolarization methods for in vivo use has raised interest in the ability to follow the physiological metabolism of choline into acetylcholine in the brain. Here we present a stable-isotope labeled choline analog, [1,1,2,2-D-4,2-C-13]choline chloride, that is suitable for this purpose. In this analog, the C-13 position showed 24% polarization in the liquid state, following DNP hyperpolarization. This nucleus also showed a long T-1 (35 s) at 11.8 T and 25 degrees C, which is a prerequisite for hyperpolarized studies. The chemical shift of this C-13 position differentiates choline and acetylcholine from each other and from the other water-soluble choline metabolites, namely phosphocholine and betaine. Enzymatic studies using an acetyltransferase enzyme showed the synthesis of the deuterated-acetylcholine form at thermal equilibrium conditions and in a hyperpolarized state. Analysis using a comprehensive model showed that the T-1 of the formed hyperpolarized [1,1,2,2-D-4,2-C-13]acetylcholine was 34 s at 14.1 T and 37 degrees C. We conclude that [1,1,2,2-D-4,2-C-13]choline chloride is a promising new molecular probe for hyperpolarized metabolic studies and discuss the factors related to its possible use in vivo. Copyright (C) 2010 John Wiley & Sons, Ltd. Supporting information may be found in the online version of this article.