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脳シグマ受容体を指標にした加齢・神経変性疾患・脳腫瘍の新しいPET診断法

以大脑西格玛受体为指标的衰老、神经退行性疾病和脑肿瘤的新型 PET 诊断方法

基本信息

批准号：
13557077
负责人：
ISHIWATA Kiichi
金额：
$ 6.78万
依托单位：
Tokyo Metropolitan Foundation for Research on Aging and Promotion of Human Welfare
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

We developed [^<11>C]SA4503 as a radioligand for mapping sigma_1 receptors in the central nervous system by positron emission tomography (PET), and successfully visualized the sigma_1 receptors in the human brain at 2000 for the first time. The purposes of the present project are 1)establishment of quantitative measurement of the brain sigma_1 receptors by PET and [^<11>C]SA4503,2)application of the [^<11>C]SA4503 PET to diagnosis of neurological and psychiatric diseases,3)basic studies on the sigma_1 receptors and 4)development of new tracers including radioligands for sigma_2 receptor subtype.We obtained the following findings.1.In general densities of neuroreceptors decrease with aging. However, the binding of radiolabeled SA4503 increased in the rat and monkey brain. The human brain also showed a similar tendency.2.In patients with Alzheimer's disease, the [^<11>C]SA4503 PET detected more sensitively degeneration of the brain than the [^<18>F]FDG PET.3.In patients with Parkinson's disease, the binding of [^<11>C]SA4503 significantly decreased in the affected than the less affected side of the anterior putamen as observed in the [^<11>C]CFT binding.4.Sigma_1 receptor occupancy by haloperidol was evaluated by [^<11>C]SA4503 PET, which would address pharmacological effects of neuroleptics in term of their sigma_1 receptor occupancy.5.The [^<11>C]SA4503 PET may be useful for patients with schizophrenia.6.The [^<11>C]SA4503 PET has potential for tumor diagnosis in the hypogastrium because of low accumulation levels of the activity.7.Brain uptake of [^<11>C]SA4503 was not mediated by P-glycoprotein.8.Several ^<11>C and ^<18>F analogs of [^<11>C]SA4503 were synthesized and evaluated in vivo. Among them we found [^<18>F]FE-SA4503 to be a promising radioligands for tumor diagnosis by PET.

我们利用正电子发射断层扫描（PET）技术开发了[^<11 b> C]SA4503作为中枢神经系统sigma_1受体的放射配体，并于2000年首次成功地在人脑中实现了sigma_1受体的可视化。本课题的目的是：1)建立PET和[^<11>C]SA4503对脑sigma_1受体的定量测定方法；2)[^<11>C]SA4503 PET在神经和精神疾病诊断中的应用；3)sigma_1受体的基础研究；4)sigma_2受体亚型放射配体等新型示踪剂的开发。我们得到了以下的发现。一般来说，神经受体的密度随着年龄的增长而下降。然而，放射性标记的SA4503在大鼠和猴脑中的结合增加。人类的大脑也表现出类似的趋势。在阿尔茨海默病患者中，[^<11>C]SA4503 PET比[^<18>F]FDG PET更敏感地检测到脑变性。在帕金森病患者中，[^<11>C]SA4503的结合在受累侧明显低于未受累侧的前壳核[^<11>C]CFT结合。用[^<11>C]SA4503 PET评价氟哌啶醇对Sigma_1受体的占用，从Sigma_1受体占用的角度探讨神经抑制剂的药理作用。[^<11>C]SA4503 PET可能对精神分裂症患者有用。[^<11>C]SA4503 PET由于其活性积累水平低，有潜在的下胃肿瘤诊断价值。[^<11 b> C]SA4503的脑摄取不受p -糖蛋白介导。合成了几种[^<11>C]SA4503的^<11>C和^<18>F类似物并在体内进行了评价。其中发现[^<18>F]FE-SA4503是一种很有前途的PET肿瘤诊断放射配体。