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DEVELOPMENT OF NOVEL RADIOPHARMACEUTICALS FOR EARLY STAGE DIAGNOSIS OF CEREBRAL NEURODEGENERATION AND FUNCTIONAL RECOVERRY AFTER INTRASTRIATAL GRAFTS

开发用于脑神经变性早期诊断和纹状移植后功能恢复的新型放射性药物

基本信息

批准号：
17390329
负责人：
KAWAI Keiichi
金额：
$ 7.69万
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：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

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 ([^<18>F]FDOPA) after 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle in rats. The brains of 6-OHDA treated rats were analyzed by tissue dissection 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 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 weeks postlesion. An increase in raclopride and a decrease in FDOPA uptake in the denervated striatum is evident even at 3 days following the 6-OHDA lesions when the degree of methamphetamine (MAP)-induced rotation is not esta … More blished. Therefore the combination of D_2 antagonist and FDOPA may provide a potentially useful method for assessing the effects of dopamine depletion in Parkinson's disease.In addition, we examined the topological specificity of MAP-induced activation of the immediate-early gene proteins, Fos and Zif268, in the nigrostriatal system in a unilateral 6-OHDA rat model of Parkinson's disease with or without intrastriatal grafts of fetal ventral mesencephalon. The differential expression of Fos and Zif268 was observed among the three regions of the nigrostriatal system following MAP in the 6-OHDA rats. This may suggest that Fos and Zif268 therefore possess gene-specific and region-specific functions in the basal ganglia nuclei.For SPECT application, radioiodinated derivatives of dopamine biosynthesis precursor, [^<123>I]I-IMT and [^<123>I]I-FTM, were evaluated as diagnosis agents for early detection of neurodegeneration. 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. 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 sensitive radiopharmaceuticals in detecting function of cerebral dopaminergic neuron. Less

研究了大鼠6-羟基多巴胺（6-OHDA）损伤后多巴胺D_1受体（[^<11>C]SCH23390）和d2受体（[^<11>C]raclopride）和多巴胺前体类似物（[^<18>F]FDOPA）的PET示踪剂分布。6-OHDA治疗大鼠脑损伤后3 d（急性期）或3周（慢性期）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完好侧。另一方面，病变后3天，病变侧纹状体中FDOPA的积累较低，病变后3周，病变侧纹状体和大脑皮层中FDOPA的积累也较低。即使在6-OHDA损伤后3天，当甲基苯丙胺（MAP）诱导的旋转程度不明显时，去神经纹状体中氯pride的增加和FDOPA摄取的减少也很明显。因此，D_2拮抗剂与FDOPA联用可能为评价多巴胺耗竭对帕金森病的影响提供一种潜在的有用方法。此外，我们在单侧6-OHDA帕金森病大鼠模型中检测了map诱导的黑质纹状体系统中直接早期基因蛋白Fos和Zif268激活的拓扑特异性，该模型有或没有胚胎腹侧中脑的纹状体内移植。6-OHDA大鼠MAP后黑质纹状体系统三个区域Fos和Zif268的表达差异。这可能表明Fos和Zif268在基底神经节核中具有基因特异性和区域特异性的功能。在SPECT应用中，多巴胺生物合成前体的放射性碘化衍生物[^<123>I]I- imt和[^<123>I]I- ftm被评价为早期检测神经变性的诊断剂。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。I-FTM与多巴胺生物合成终酶有亲和关系，对急性期神经变性检测敏感。因此，I-IMT和I-FTM可能是检测大脑多巴胺能神经元功能的敏感放射性药物的新候选物。少