[11C]CURB: Evaluation of a novel radiotracer for imaging fatty acid amide hydrolase by positron emission tomography
[11C]CURB: Evaluation of a novel radiotracer for imaging fatty acid amide hydrolase by positron emission tomography
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DOI：
10.1016/j.nucmedbio.2010.08.001
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发表时间：
2011-02-01
影响因子：
3.1
通讯作者：
Vasdev, Neil
中科院分区：
文献类型：
--
作者：
Wilson, Alan A.;Garcia, Armando;Vasdev, Neil
脂肪酸酰胺水解酶（Fatty acid amide hydrolase， FAAH）是负责代谢内源性大麻素anandamide的酶，因此是分子成像的重要靶标。迄今为止，没有放射性示踪剂被证明是有用的成像FAAH使用正电子发射断层扫描（PET）或单光子发射计算机断层扫描（SPECT）。我们在此通过体外生物分布研究和药理学挑战来确定一种新型碳-11标记的FAAH抑制剂的适用性。方法：将一种有效的不可逆FAAH抑制剂URB694通过尾静脉注射给雄性大鼠，在羰基位置用碳-11放射性标记（[C-11]CURB）。注射后各时间点处死大鼠，解剖组织标本，计数称重。用URB694或URB597预处理动物，研究其与FAAH的特异性结合。为了进行代谢和结合机制的研究，我们在注射放射性示踪剂后切除全脑，用80%的乙腈进行匀浆和完全提取，以测定与脑实质不可逆结合的放射性的时间过程和比例。结果：经大鼠静脉注射后，[C-11]CURB表现出较高的脑摄取[5 min时标准摄取值（SUV） 1.6-2.4]，且随着时间的推移几乎没有洗脱，具有不可逆结合的特点。在皮质中观察到最高的放射性吸收，在小脑中处于中等水平，在下丘脑中最低，反映了报道的FAAH的分布。通过增加URB694的剂量预处理，脑对放射性的摄取呈剂量依赖性，表明其结合是饱和的。用表征良好的FAAH抑制剂URB597预处理后，所有脑区的结合减少了70-80%。均质脑提取实验明确表明[C-11]CURB与FAAH不可逆结合。结论：基于清醒大鼠脑的离体生物分布研究，标题示踪剂显示出良好的脑摄取，区域异质性和结合特异性等有利特性。[C-11]CURB是一种非常有前途的FAAH PET成像放射性示踪剂。(C) 2011爱思唯尔公司版权所有。
Introduction: Fatty acid amide hydrolase (FAAH) is the enzyme responsible for metabolising the endogenous cannabinoid, anandamide, and thus represents an important target for molecular imaging. To date, no radiotracer has been shown to be useful for imaging of FAAH using either positron emission tomography (PET) or single photon emission computed tomography (SPECT). We here determine the suitability of a novel carbon-11-labeled inhibitor of FAAH via ex vivo biodistribution studies in rat brain in conjunction with pharmacological challenges.Methods: A potent irreversible inhibitor of FAAH, URB694, radiolabeled with carbon-11 in the carbonyl position ([C-11]CURB), was administered to male rats via tail-vein injection. Rats were sacrificed at various time points postinjection, and tissue samples were dissected, counted and weighed. Specific binding to FAAH was investigated by pretreatment of animals with URB694 or URB597. For metabolism and mechanism of binding studies, whole brains were excised post-radiotracer injection, homogenised and extracted exhaustively with 80% aq. acetonitrile to determine the time course and fraction of radioactivity that was irreversibly bound to brain parenchyma.Results: Upon intravenous injection into rats, [C-11]CURB showed high brain uptake [standard uptake value (SUV) of 1.6-2.4 at 5 min] with little washout over time, which is characteristic of irreversible binding. Highest uptake of radioactivity was seen in the cortex, intermediate in the cerebellum and lowest in the hypothalamus, reflecting the reported distribution of FAAH. Brain uptake of radioactivity was decreased in a dose-dependent manner by pretreatment with increasing amounts of URB694, demonstrating that binding was saturable. Pretreatment with the well-characterised FAAH inhibitor, URB597, reduced binding in all brain regions by 70-80%. Homogenised brain extraction experiments demonstrated unequivocally that [C-11]CURB was irreversibly bound to FAAH.Conclusions: The title radiotracer demonstrates favourable properties such as good brain uptake, regional heterogeneity and specificity of binding based on ex vivo biodistribution studies in conscious rat brain. [C-11]CURB represents a highly promising radiotracer for the imaging of FAAH using PET. (C) 2011 Elsevier Inc. All rights reserved.