Change in the Binding of [11C]BU99008 to Imidazoline I2 Receptor Using Brain PET in Zucker Rats
Change in the Binding of [11C]BU99008 to Imidazoline I2 Receptor Using Brain PET in Zucker Rats
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DOI：
10.1007/s11307-018-1206-y
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发表时间：
2019-02-01
影响因子：
3.1
通讯作者：
Zhang, Ming-Rong
中科院分区：
文献类型：
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作者：
Kawamura, Kazunori;Yamasaki, Tomoteru;Zhang, Ming-Rong
咪唑啉I-2受体（imdazoline I-2 receptor，I2 R）存在于下丘脑等脑摄食中枢，其配体具有刺激摄食的作用。因此，有人提出I2 R可能在摄食控制中起作用。[C-11] BU 99008被开发为用于I2 R成像的正电子发射断层扫描（PET）示踪剂。在临床前研究中，通过脑PET研究，[C-11] BU 99008显示出相对较高的脑渗透性和特异性结合。本研究采用[C-11] BU 99008对肥胖大鼠进行定量PET研究，评价肥胖引起的与I2 R功能相关的病理状态。方法对Zucker（ZUC）瘦大鼠和肥胖大鼠进行PET扫描，测定血浆放射性和代谢产物，结果注射[C-11]后，BU 99008在ZUC瘦大鼠和肥胖大鼠下丘脑中均高度蓄积，然后逐渐减少，直至注射后60 min。注射后30 ~ 60 min，ZUC肥胖大鼠下丘脑内累积放射性是瘦大鼠的1.3倍。分布容积（V-T）估计的Logan图形分析中的ZUC肥胖大鼠的下丘脑是1.8倍以上的ZUC瘦大鼠。在代谢物分析中，注射后60 min ZUC肥胖大鼠血浆中原型的百分比（5.0%）显著低于瘦大鼠（9.1%）。结论通过[C-11] BU 99008 PET显像，我们证实ZUC瘦大鼠摄食中心的累积放射性和估计的V-T值低于肥胖大鼠。使用[C-11] BU 99008的PET研究可能有助于阐明肥胖引起的与I2 R功能相关的病理状况。
PurposeThe imdazoline I-2 receptor (I2R) has been found in the feeding centers of the brain, such as the hypothalamus, and certain I2R ligands have been reported to stimulate food intake. Thus, it has been proposed that I2R may play a role in feeding control. [C-11]BU99008 was developed as a positron emission tomography (PET) tracer for imaging of I2R. [C-11]BU99008 displayed relatively high brain penetration and specific binding by brain PET studies in preclinical studies. Here, we evaluated a pathological condition caused by obesity related to I2R function by quantitative PET study using [C-11]BU99008.ProceduresPET scans were acquired in the Zucker (ZUC) lean and fatty rats, radioactivity and metabolites of plasma were measured, and the kinetic parameters were estimated.ResultsRadioactivity levels after the injection of [C-11]BU99008 in the hypothalamus of both ZUC lean and fatty rats were highly accumulated, and then gradually decreased until 60min after the injection. The accumulated radioactivity from 30 to 60min after the injection in the hypothalamus of the ZUC fatty rats was 1.3 times greater than that of lean rats. The volume of distribution (V-T) estimated by Logan graphical analysis in the hypothalamus of the ZUC fatty rats was 1.8 times greater than that in the ZUC lean rats. In metabolite analysis, the percentages of the unchanged form in the plasma of the ZUC fatty rats at 60min after the injection (5.0%) was significantly lower than that of lean rats (9.1%).ConclusionsBy PET imaging using [C-11]BU99008, we demonstrated that the accumulated radioactivity and estimated V-T value in the feeding center of ZUC lean rats was lower than that in fatty rats. PET studies using [C-11]BU99008 may contribute to elucidate a pathological condition caused by obesity related to I2R function.