IN-VIVO PROBES OF NIGROSTRIATAL CELL DEGENERATION

黑质纹状体细胞变性的体内探针

• 批准号: 2714545
• 负责人: JORGE R BARRIO
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2714545
• 关键词: Parkinson's disease; Primates; aromatic L aminoacid decarboxylase; cell death; central neural pathway /tract; corpus striatum; disease /disorder model; dopamine; dopamine receptor; enzyme activity; methylphenyltetrahydropyridine; neural degeneration; neurochemistry; neurotransmitter transport; positron emission tomography; substantia nigra

DESCRIPTION (Investigator's Abstract): The central hypothesis of this work is that radiolabeled enzyme markers of presynaptic dopaminergic function used with positron emission tomography (PET) are not linear indicators of nigrostriatal cell losses. It is expected that axonal sprouting with synapses would respond quickly to early signs of nigrostriatal dopaminergic degeneration as part of the compensatory mechanisms at play to maintain functional activity. If so, substantial changes in aromatic amino acid decarboxylase (AAAD) activities and dopamine reuptake sites are not expected to occur during this adjustment period and, therefore, the AAAD-dependent kinetics and dopamine reuptake ligand binding will not be sensitive to these initial changes. To test this hypothesis, we will use the MPTP-monkey-model of Parkinson's disease (both symptomatic and asymptomatic) to correlate in a controlled environment the graded effects of nigrostriatal cell loss on presynaptic function with the biochemistry and central kinetics of the radiolabeled probes. We will focus our in on the initial stages of cell degeneration, with the aim of providing probes that will detect vestigation neurochemical deficiencies preceding clinical symptoms. We will combine the unique expertise and resources of two leading centers in the world, namely the Parkinson's Institute (Dr. W. Langston, ector) in I methyl-4- phenyl- I ,2,3,6 tetrahydropyridine (MPTP)-exposure to non-humans primates and humans, and UCLA, in functional imaging with positron emission tomography. With a "gold standard" provide-by concomitant cytological and neurochemical information, in-vivo PET data will be correlated with the functional integrity of the dopaminergic system. If this work is successful, we will have developed new in-vivo approaches to: 1) unveil otherwise undetected, early signs of nigrostriatal cell degeneration; 2) trace striatal AAAD activity allowing for evaluation of specific pharmacological interactions (e.g., methamphetamine) and the effects of cell degeneration. The combination of dopamine enzyme probes and, net dopamine re-uptake ligands ("cocaine receptor" ligands), will provide the necessary tools and contribute to the logic necessary for the non-invasive evaluation of the functional activity of central dopaminergic mechanisms in health disease states.

描述（研究者的摘要）：此的中心假设 工作是突触前多巴胺能的放射性标记酶标记 正电子发射断层扫描（PET）使用的功能不是线性的 黑质细胞损失的指标。预计轴突 突触发芽会迅速响应的早期迹象 黑质纹状体多巴胺能变性作为补偿性的一部分 发挥作用的机制以维持功能活性。如果是这样，则很大 芳香氨基酸脱羧酶（AAAD）活性的变化和 在此调整期间，预计多巴胺的再摄取部位不会发生 因此，依赖于AAAD的动力学和多巴胺再摄取时期 配体结合对这些初始变化不会敏感。 为了检验这一假设，我们将使用帕金森氏症的MPTP-MONKEY-MODEL 疾病（有症状和无症状）与受控的 环境斑纹细胞损失对突触前的分级影响 具有放射性标记的生物化学和中央动力学的功能 探针。我们将集中在细胞变性的初始阶段， 目的是提供可以检测归属率的探针 临床症状之前的神经化学缺陷。我们将结合 世界两个主要中心的独特专业知识和资源， 即帕金森研究所（帕金森研究所（W. Langston） 苯基i，2,3,6四氢吡啶（MPTP） - 暴露于非人类 灵长类动物和人类以及UCLA，在功能成像中具有正电子成像 排放断层扫描。带有“黄金标准”提供 细胞学和神经化学信息，体内PET数据将是 与多巴胺能系统的功能完整性相关。 如果这项工作成功，我们将开发新的体内 方法： 1）否则未被发现，斑纹细胞的早期迹象 退化; 2）痕量纹状体AAAD活性，允许评估特定 药理相互作用 （例如，甲基苯丙胺）和细胞变性的作用。 多巴胺酶探针和净多巴胺再摄取的结合 配体（“可卡因受体”配体）将提供必要的工具 并有助于非侵入性评估所必需的逻辑 中央多巴胺能在健康中的功能活性 疾病状态。

项目成果

Nigrostriatal reduction of aromatic L-amino acid decarboxylase activity in MPTP-treated squirrel monkeys: in vivo and in vitro investigations.

MPTP 处理的松鼠猴中芳香族 L-氨基酸脱羧酶活性的黑质纹状体降低：体内和体外研究。

• DOI: 10.1046/j.1471-4159.2000.741147.x
• 发表时间: 2000
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Yee,RE;Huang,SC;Stout,DB;Irwin,I;Shoghi-Jadid,K;Togaski,DM;DeLanney,LE;Langston,JW;Satyamurthy,N;Farahani,KF;Phelps,ME;Barrio,JR
• 通讯作者: Barrio,JR

Synthesis of 3beta-(4-[18F]fluoromethylphenyl)- and 3beta-(2-[18F] fluoromethylphenyl)tropane-2beta-carboxylic acid methyl esters: new ligands for mapping brain dopamine transporter with positron emission tomography.

3β-(4-[18F]氟甲基苯基)-和3β-(2-[18F]氟甲基苯基)托烷-2β-羧酸甲酯的合成：用正电子发射断层扫描绘制脑多巴胺转运蛋白的新配体。

• DOI: 10.1016/s0969-8051(99)00023-2
• 发表时间: 1999
• 期刊: Nuclear medicine and biology
• 影响因子: 3.1
• 作者: Petric,A;Barrio,JR;Namavari,M;Huang,SC;Satyamurthy,N
• 通讯作者: Satyamurthy,N

2Beta-carbomethoxy-3beta-(4- and 2-[18F]fluoromethylphenyl)tropanes: specific probes for in vivo quantification of central dopamine transporter sites.

2β-甲甲氧基-3β-（4-和2-[18F]氟甲基苯基）托烷：用于体内定量中央多巴胺转运蛋白位点的特异性探针。

• DOI: 10.1016/s0969-8051(99)00073-6
• 发表时间: 1999
• 期刊: Nuclear medicine and biology
• 影响因子: 3.1
• 作者: Stout,D;Petric,A;Satyamurthy,N;Nguyen,Q;Huang,SC;Namavari,M;Barrio,JR
• 通讯作者: Barrio,JR

Novel observations with FDOPA-PET imaging after early nigrostriatal damage.

早期黑质纹状体损伤后 FDOPA-PET 成像的新观察。

• DOI: 10.1002/mds.1168
• 发表时间: 2001
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Yee,RE;Irwin,I;Milonas,C;Stout,DB;Huang,SC;Shoghi-Jadid,K;Satyamurthy,N;Delanney,LE;Togasaki,DM;Farahani,KF;Delfani,K;Janson,AM;Phelps,ME;Langston,JW;Barrio,JR
• 通讯作者: Barrio,JR

Synthesis of stereo (R and S) and geometric (E and Z) isomers of [18F]fluoro-beta-fluoromethylene-m-tyrosine derivatives: in vivo probes of central dopaminergic function.

[18F]氟-β-氟亚甲基-间-酪氨酸衍生物的立体（R和S）和几何（E和Z）异构体的合成：中枢多巴胺能功能的体内探针。

• DOI: 10.1016/s0969-8051(99)00006-2
• 发表时间: 1999
• 期刊: Nuclear medicine and biology
• 影响因子: 3.1
• 作者: Lacan,G;Satyamurthy,N;Barrio,JR
• 通讯作者: Barrio,JR