权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

DEVELOPMENT OF NOVEL RADIOPHARMACEUTICALS FOR EARLY STAGE DIAGNOSIS OF CEREBRAL NEURODEGENERATION.

开发用于脑神经退行性早期诊断的新型放射性药物。

基本信息

批准号：
14370273
负责人：
KAWAI Keiichi
金额：
$ 5.12万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370273/
关键词：
Neurodegeneration Early detection Parkinsonism model rat Dopaminergic neuron Dopamine receptor Amino acid transport Dopa decarboxylase Imaging diagnosis 脳内ドーパミン神経路線条体

项目摘要

We studied the PET tracer distributions of ligands for dopamine D_1 receptors ([^<11>C]SCH23390) and D_2 receptors ([^<11>C]raclopride) and of the dopamine precursor analog 6-[^<18>F]fluoro-L-3,4-dihydroxyphenylalanine ([^<18>F]FDOPA) in the brain after 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle in rats. The number of methamphetamine-induced rotation was higher at 14 days than that at 3 days following the 6-OHDA lesions. The brains of 6-OHDA treated rats were analyzed by tissue dissection following i.v.bolus of each tracer at 3 days (acute stage) or 3 weeks (chronic stage) postlesion. [^<11>C]Raclopride, but not [^<11>C]SCH23390,showed a higher accumulation in the striatum on the lesion side compared with that on the non-lesioned (intact) side both 3 days and 3 weeks postlesion. On the other hand, a lower accumulation of [^<18>F]FDOPA was found in the striatum on the lesion side 3 days postlesion, and both in the striatum and cerebral cortex on the lesion side 3 … More weeks postlesion. Our studies demonstrate that an increase in [^<11>C]raclopride and a decrease in [^<18>F]FDOPA uptake in the denervated striatum is evident even at 3 days following the 6-OHDA lesions when the degree of methamphetamine-induced rotation is not established. Therefore the combination of a D_2 antagonist and FDOPA may provide a potentially useful method for assessing the effects of dopamine depletion in Parkinson's disease.For SPECT application, radioiodinated derivatives of L-tyrosine, dopamine biosynthesis precursor, were evaluated as diagnosis agents for early detection of neurodegeneration. 3-[^<123>I]iodo-α-methyl-L-tyrosine (I-IMT) and 3-[^<123>I]iodo-α-difluoromethyl-tyrosine methyl ester (I-FTM) were selected as SPECT imaging agents for cerebral amino acid transpoter and dopa decarboxylase (DDC) activity. In the biodistribution study, I-IMT accumulation in the striatum on the lesion side 3 days postlesion increased, then decreased in 2 weeks postlesion, compared with the intact side. On the other hand, I-FTM showed a lower accumulation in the striatum on the lesion side compared with that on the intact side both 3 days and 2 weeks postlesion. It shows that I-FTM, with an affinity to the final enzyme of dopamine biosynthesis, was sensitive for detection of neurodegeneration in acute stage. Thus, both I-IMT and I-FTM may be new candidates of radiopharmaceuticals that can be useful in assessing function of cerebral dopaminergic neuron. Less

研究了多巴胺D_1受体（[^<11>C]SCH23390）和d2受体（[^<11>C]raclopride）以及多巴胺前体类似物6-[^<18>F]氟- l -3,4-二羟基苯丙氨酸（[^<18>F]FDOPA）在大鼠内侧前脑6-羟基多巴胺（6- ohda）损伤后的PET示踪剂分布。甲基苯丙胺诱导的轮换次数在6-OHDA病变后第14天高于第3天。在损伤后3天（急性期）或3周（慢性期），分别给药6-OHDA治疗的大鼠进行脑组织解剖分析。[^<11>C]Raclopride，而不是[^<11>C]SCH23390，在病变后3天和3周均显示病变侧纹状体的积累高于未病变（完整）侧。另一方面，在病变后3天，病变侧纹状体中发现了较低的[^<18>F]FDOPA积累，病变后3周，病变侧纹状体和大脑皮层中都发现了较低的FDOPA积累。我们的研究表明，即使在6-OHDA损伤后3天，当甲基苯丙胺诱导的旋转程度尚未确定时，去神经纹状体中[^<11>C]的雷氯pride增加和[^<18>F]的FDOPA摄取也明显减少。因此，D_2拮抗剂与FDOPA联用可能为评估多巴胺耗竭对帕金森病的影响提供一种潜在的有用方法。对于SPECT应用，多巴胺生物合成前体l -酪氨酸的放射性碘化衍生物被评估为早期检测神经变性的诊断试剂。选择3-[^<123>I]碘-α-甲基- l-酪氨酸（I- imt）和3-[^<123>I]碘-α-二氟甲基酪氨酸甲酯（I- ftm）作为脑氨基酸转位和多巴脱羧酶（DDC）活性的SPECT显像剂。在生物分布研究中，病变侧纹状体的I-IMT积累在病变后3天增加，然后在病变后2周减少。另一方面，在病变3天和2周后，I-FTM在病变侧纹状体中的积累均低于完好侧。结果表明，I-FTM与多巴胺生物合成终酶有亲和关系，对急性期神经退行性疾病检测敏感。因此，I-IMT和I-FTM可能是评估大脑多巴胺能神经元功能的放射性药物的新候选物。少