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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

我们研究了6-羟基多巴胺(6-OHDA)损毁大鼠前脑内侧束后，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(FDOPA)的PET示踪分布。6-OHDA处理组大鼠在损伤后3天(急性期)和3周(慢性期)进行脑组织切片分析。[^&lt；11&gt；C]在损伤后3天和3周，[^&lt；11&gt；C][^&lt；11&gt；C]SCH23390[^&lt；11&gt；C][^&lt；11&gt；C][^&lt；11&gt；C]SCH23390在损伤侧纹状体内的蓄积均高于健侧。另一方面，损伤后3天，损伤侧纹状体内[FDOPA]的积聚较少，损伤后3周，损伤侧纹状体和大脑皮质中的[FDOPA]积聚较少。在甲基苯丙胺(MAP)诱导的旋转程度不是esta…的情况下，即使在6-ohda损伤后3天，失神经纹状体中拉氯必利的增加和fda摄取的减少也是明显的。更多的污点。因此，D2拮抗剂和FDOPA的结合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。此外，我们在单侧6-OHDA帕金森病大鼠模型中检测了MAP诱导黑质纹状体系统即刻早期基因蛋白Fos和Zif268激活的拓扑特异性。在6-OHDA大鼠MAP后，观察到Fos和Zif268在黑质纹状体系统的三个区域的差异表达。这可能表明Fos和Zif268在基底节具有基因特异性和区域特异性功能。在SPECT应用中，放射性碘标记的多巴胺生物合成前体衍生物[^&lt；123&gt；i]i-IMT和[^&lt；123&gt；i]i-FTM被评价为神经变性的早期诊断试剂。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。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敏感指标。因此，I-IMT和I-FTM都可能成为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者。较少