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

我们开发了[^&lt；11&gt；C]SA4503作为放射性配基，用于通过正电子发射断层扫描(PET)定位中枢神经系统中的sigma_1受体，并于2000年首次在人脑中成功地显示了sigma_1受体。本项目的目的是：1)建立脑组织Sigma_1受体的PET和SA4503定量测定方法；2)将Sigma_1受体应用于神经和精神疾病的诊断；3)Sigma_1受体的基础研究；4)开发包括Sigma_2受体亚型放射性配体在内的新示踪剂。然而，放射性标记的SA4503在大鼠和猴脑中的结合增加。2.在阿尔茨海默病患者中，[11&>C]SA4503PET比FDG PET更敏感地检测到大脑的变性。3.在帕金森病患者中，[^&lt；11&gt；C]SA4503在患侧前壳核的结合明显低于受影响较轻的一侧。4.用氟哌啶醇评估Sigma_1受体的占有率5.SA4503PET可能对精神分裂症患者有用。6.由于活性蓄积水平低，SA4503PET有可能用于下腹部肿瘤的诊断。7.大脑摄取SA4503不是由P-糖蛋白介导的。合成了F类似物[^&lt；11&gt；C]SA4503，并对其进行了体内评价。其中，我们发现[FE-SA4503]是一种很有前途的PET诊断肿瘤的放射性配体。

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.