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

我们研究了多巴胺D_1受体（[^<11>C] SCH 23390）和D_2受体（[^<11>C]雷氯必利）的配体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6-羟基多巴胺（6-OHDA）损毁大鼠内侧前脑束后脑内的PET示踪分布。甲基苯丙胺诱导的旋转次数在6-OHDA损伤后14天高于3天。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，通过组织解剖分析6-OHDA处理的大鼠的脑。[^<11>C]Raclopride，而不是[^<11>C] SCH 23390，在损伤侧的纹状体中的蓄积高于损伤后3天和3周的非损伤侧（完整侧）。另一方面，<18>损伤后3天在损伤侧的纹状体中发现较低的[^ F]FDOPA积累，并且在损伤侧的纹状体和大脑皮层中均发现较低的[^F]FDOPA积累 ...更多信息 损伤后2周。我们的研究表明，<11><18>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[^ C]雷氯必利的增加和[^ F]FDOPA摄取的减少也是明显的。因此，D_2拮抗剂和FDOPA的联合应用可能为评估多巴胺耗竭在帕金森病中的作用提供一种潜在的有用方法。在SPECT应用方面，放射性碘标记的多巴胺生物合成前体L-酪氨酸衍生物被评估为早期检测神经变性的诊断剂。选择3-碘<123>-α-甲基-L-酪氨酸（I-IMT）和3-碘<123>-α-二氟甲基-酪氨酸甲酯（I-FTM）作为脑氨基酸转运蛋白和多巴脱羧酶（DDC）活性的SPECT显像剂。在生物分布研究中，与完整侧相比，损伤侧纹状体中的I-IMT在损伤后3天增加，然后在损伤后2周减少。另一方面，I-FTM在损伤侧纹状体中的蓄积量低于损伤侧，损伤后3天和2周均如此。结果表明，I-FTM对多巴胺生物合成的终末酶具有亲和力，对急性期神经退行性变的检测敏感。因此，I-IMT和I-FTM可能是评价脑多巴胺能神经元功能的放射性药物的新候选者。少

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