使用 [¹⁸F]mefway PET 评估啮齿动物模型中的 5-羟色胺 5-HT(1A) 受体。
Evaluation of serotonin 5-HT(1A) receptors in rodent models using [¹⁸F]mefway PET.
机构信息
Preclinical Imaging, Department of Radiological Sciences, University of California, Irvine, California, USA.
出版信息
Synapse. 2013 Sep;67(9):596-608. doi: 10.1002/syn.21665. Epub 2013 Apr 18.
INTRODUCTION
Serotonin 5-HT(1A) receptors have been investigated in various CNS disorders, including epilepsy, mood disorders, and neurodegeneration. [¹⁸F]Mefway (N-{2-[4-(2'-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(cis/trans-4'-[¹⁸F]fluoromethylcyclohexane)-carboxamide) has been developed as a suitable positron emission tomography (PET) imaging agent for these receptors. We have now evaluated the suitability of [¹⁸F]trans-mefway in rat and mouse models using PET and computerized tomography (CT) imaging and corroborated with ex vivo and in vitro autoradiographic studies.
METHODS
Normal Sprague-Dawley rats and Balb/C mice were used for PET/CT imaging using intravenously injected [¹⁸F]trans-mefway. Brain PET data were coregistered with rat and mouse magnetic resonance imaging template and regional distribution of radioactivity was quantitated. Selected animals were used for ex vivo autoradiographic studies to confirm regional brain distribution and quantitative measures of binding, using brain region to cerebellum ratios. Binding affinity of trans-mefway and WAY-100635 was measured in rat brain homogenates. Distribution of [¹⁸F]trans-4-fluoromethylcyclohexane carboxylate ([¹⁸F]FMCHA), a major metabolite of [¹⁸F] trans-mefway, was assessed in the rat by PET/CT.
RESULTS
The inhibition constant, K(i) for trans-mefway was 0.84 nM and that for WAY-100635 was 1.07 nM. Rapid brain uptake of [¹⁸F]trans-mefway was observed in all rat brain regions and clearance from cerebellum was fast and was used as a reference region in all studies. Distribution of [¹⁸F]trans-mefway in various brain regions was consistent in PET and in vitro studies. The dorsal raphe was visualized and quantified in the rat PET but identification in the mouse was difficult. The rank order of binding to the various brain regions was hippocampus > frontal cortex > anterior cingulate cortex > lateral septal nuclei > dorsal raphe nuclei.
CONCLUSION
[¹⁸F]trans-Mefway appears to be an effective 5-HT(1A) receptor imaging agent in rodents for studies of various disease models.
简介
血清素 5-HT(1A)受体已在包括癫痫、情绪障碍和神经退行性变在内的各种中枢神经系统疾病中进行了研究。[¹⁸F]Mefway（N-{2-[4-(2'-甲氧基苯基)哌嗪基]乙基}-N-(2-吡啶基)-N-(顺/反-4'-[¹⁸F]氟甲基环己烷)-甲酰胺）已被开发为用于这些受体的合适正电子发射断层扫描（PET）成像剂。我们现在已经使用 PET 和计算机断层扫描（CT）成像评估了 [¹⁸F]trans-mefway 在大鼠和小鼠模型中的适用性，并通过离体和体外放射自显影研究进行了证实。
方法
正常 Sprague-Dawley 大鼠和 Balb/C 小鼠通过静脉内注射 [¹⁸F]trans-mefway 进行 PET/CT 成像。脑 PET 数据与大鼠和小鼠磁共振成像模板进行配准，并定量定量测定放射性分布。选择部分动物进行离体放射自显影研究，以使用脑区与小脑的比值来确认脑区分布和结合的定量测量。使用大鼠脑匀浆测量 trans-mefway 和 WAY-100635 的结合亲和力。通过 PET/CT 在大鼠中评估[¹⁸F]trans-4-氟甲基环己烷羧酸酯([¹⁸F]FMCHA）的主要代谢产物[¹⁸F]trans-mefway 的分布。
结果
trans-mefway 的抑制常数，K(i)为 0.84 nM，WAY-100635 的 K(i)为 1.07 nM。在所有大鼠脑区中均观察到 [¹⁸F]trans-mefway 的快速脑摄取，小脑清除速度较快，在所有研究中均用作参考区。在 PET 和体外研究中，[¹⁸F]trans-mefway 在各种脑区的分布一致。在大鼠 PET 中可以观察到背侧中缝核并进行定量，但在小鼠中难以识别。对各种脑区的结合的排序为海马体 > 额叶皮层 > 前扣带皮层 > 外侧隔核 > 背侧中缝核。
结论
[¹⁸F]trans-Mefway 似乎是一种有效的 5-HT(1A)受体成像剂，可用于啮齿动物的各种疾病模型研究。
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