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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

我们研究了6-羟基多巴胺(6-OHDA)损毁大鼠内侧前脑束后，多巴胺D_1受体(11&gt；11&gt；C)和D_2受体(11&gt；C)配体以及多巴胺前体类似物6-[^&lt；18&gt；F]fluoro-L-3，4-dihydroxyphenylalanine([^&lt；18&gt；F]FDOPA)在脑内的分布。6-OHDA损毁后第14天甲基苯丙胺诱发的旋转次数高于第3天。6-OHDA处理组大鼠在损伤后3天(急性期)或3周(慢性期)静脉注射每种示踪剂后进行组织切片分析。在损伤后3天和3周，[^&lt；11&gt；C]而不是[^&lt；11&gt；C]SCH23390在损伤侧纹状体内的蓄积均高于非损伤侧(未损伤侧)。另一方面，在损伤后3天，损伤侧纹状体内的FDOPA积聚较少，损伤侧3…的纹状体和大脑皮质中也有较低的积聚更多的损伤后几周。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，失神经纹状体中[^&lt；11&gt；C]雷氯普利的增加和[^&lt；18&gt；F]FDOPA摄取的减少也是明显的。因此，D2拮抗剂和FDOPA的联合应用可能为评估多巴胺缺乏在帕金森病中的作用提供一种潜在的有用方法。在SPECT应用中，放射性碘标记的L酪氨酸衍生物，多巴胺生物合成前体，被评估为早期检测神经变性的诊断试剂。3-碘-甲基-L酪氨酸(I-IMT)和3-[^&lt；123&gt；I]iodo-α-difluoromethyl-tyrosine甲酯(I-α)作为脑内氨基酸转运体和多巴脱羧酶(DDC)的SPECT显像剂。在生物分布研究中，与健侧相比，损伤侧纹状体I-IMT积聚在损伤后3天增加，2周后减少。而损伤后3天和2周，I-FTM在损伤侧纹状体的积聚均低于健侧。结果表明，I-FTM与多巴胺生物合成的终末酶有亲和力，是检测急性期神经退行性变的灵敏方法。因此，I-IMT和I-FTM都可能成为新的放射性药物候选药物，可用于评估大脑多巴胺能神经元的功能。较少