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

我们研究了多巴胺 D_1 受体 ([^<11>C]SCH23390) 和 D_2 受体 ([^<11>C]雷氯必利) 配体以及多巴胺前体类似物 6-[^<18>F] 的 PET 示踪剂分布6-羟基多巴胺后大脑中的氟-L-3，4-二羟基苯丙氨酸（[^ 18 F]FDOPA）大鼠内侧前脑束的 (6-OHDA) 损伤甲基苯丙胺诱导的旋转次数在 6-OHDA 损伤后第 14 天高于第 3 天。对接受治疗的 6-OHDA 大鼠的大脑进行了组织分析。 [^<11>C]雷氯必利在静脉注射每种示踪剂后 3 天（急性期）或 3 周（慢性期）进行解剖。 [^11C]SCH23390，在病变后3天和3周，与未病变（完整）侧相比，在病变侧纹状体中显示出较高的积累，另一方面，[的积累较低。 ^<18>F]FDOPA在病灶后3天的病灶侧纹状体中发现，并且在病灶侧3周的纹状体和大脑皮层中均发现我们的研究表明，即使在6-OHDA损伤后3天，去神经纹状体中[^ 11 C]雷氯必利的增加和[^ 18 F]FDOPA摄取的减少也是明显的。甲基苯丙胺诱导的旋转尚未确定，因此 D_2 拮抗剂和 FDOPA 的组合可能为评估多巴胺耗竭对帕金森病的影响提供潜在有用的方法。 SPECT应用，L-酪氨酸（多巴胺生物合成前体）的放射性碘化衍生物，被评估为神经变性早期检测的诊断剂3-[^123I]碘-α-甲基-L-酪氨酸（I-IMT）和3。选择-[^123I]碘-α-二氟甲基酪氨酸甲酯(I-FTM)作为脑氨基酸SPECT显像剂在生物分布研究中，与完好侧相比，损伤侧纹状体中 I-IMT 的积累在损伤后 3 天增加，然后在损伤后 2 周减少。病变后 3 天和 2 周，与完整侧相比，FTM 在病变侧纹状体中的积累量较低，这表明 I-FTM 对 I-FTM 具有亲和力。多巴胺生物合成的最终酶，对急性期神经变性的检测很敏感，因此，I-IMT 和 I-FTM 可能是可用于评估大脑多巴胺能神经元功能的新候选放射性药物。