ALTROPANE, SPECT OR PET IMAGING PROBE FOR DOPAMINE NEURONS III: PARKINSONS BRAIN

用于多巴胺神经元 III 的阿托烷、SPECT 或 PET 成像探针:帕金森病大脑

基本信息

  • 批准号:
    6277800
  • 负责人:
  • 金额:
    $ 3.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1998
  • 资助国家:
    美国
  • 起止时间:
    1998-05-01 至 1999-04-30
  • 项目状态:
    已结题

项目摘要

Increasing evidence suggests that the dopamine transporter is situated almost exclusively on dopamine neurons. Accordingly, it is an excellent marker for Parkinson's disease, a neurodegenerative disease characterized by a severe loss of dopamine neurons. We previously demonstrated that the potent dopamine transport inhibitor [125I]altropane (IACFT:E-N-iodoallyl-2 -carbomethoxy-3 -(4-fluorophenyl)tropane) is a high affinity selective probe for the dopamine transporter in monkey brain and an effective SPECT imaging agent in nonhuman primate brain. This project had two objectives, to determine whether the favorable binding properties of altropane in nonhuman primates extends to human brain and to assess the suitability of altropane as a marker for Parkinson's diseased brain. In homogenates of human brain putamen, [125I]altropane bound to a single high affinity site (KD 4.96 q 0.38 nM, n = 4) and a site density (BMAX 212 q 41.1 pmol/g original wet tissue weight). The affinity was within the range of affinities reported for effective brain imaging agents and, equally significant, binding to a single affinity site increases the level of accuracy for density measurements. The density was within the density range reported previously for the dopamine transporter in this brain region. Drugs inhibited [125I]altropane binding with a rank order of potency that corresponded closely to their rank order for blocking dopamine transport (r 0.98, p <0.001). In post-mortem Parkinson's diseased brain, bound [125I]altropane (1 nM) was markedly reduced (89%, 99% in putamen, depending on measures of non-specific binding) compared with normal aged-matched controls (normal putamen 49.2 q 8.1 pmol/g ; Parkinson's diseased putamen 0.48q0.33 pmol/g; n = 4). In vitro autoradiography, conducted in tissue sections at a single plane of the basal ganglia, revealed high levels of [125I]altropane binding the caudate nucleus and putamen, but lower levels (73% of the caudate-putamen) in the nucleus accumbens (n = 7). In Parkinson's diseased brains (n = 4), [125I]altropane binding was 13% of the levels detected in normal putamen, 17% of normal values in the caudate nucleus and 25% of normal levels in nucleus accumbens. Accordingly, [125I]altropane detected losses of the dopamine transporter that are consistent with dopamine depletion reported previously. The association of [125I]altropane to the dopamine transporter in human post-mortem tissue, the marked reduction of [125I]altropane binding in Parkinson's diseased brains, its rapid entry into brain and highly localized distribution in dopamine-rich brain regions, support its use as a probe for monitoring the dopamine transporter and associated dopamine neurons in vitro and in vivo by SPECT or PET imaging technologies. As an in vivo imaging agent, altropane displays favorable pharmacokinetic properties, achieving equilibrium with the primate brain dopamine transporter within 30 - 60 minutes. These properties are well suited to both PET and SPECT imaging. In concert with this advantage is the feasibility of converting altropane into a chemically identical PET ([11C] or SPECT (123I]) imaging agent. A detailed assessment and comparison of PET vs SPECT imaging conducted under identical conditions with altropane is ongoing. Imaging of the dopamine transporter with WIN 35,428 and its congeners has been applied to the aging brain, Parkinson's disease, other neuropsychiatric disorders (e.g. Tourette's disorder, Lesch-Nyhan syndrome, and alcohol abuse. Investigation of the dopamine transporter as a target of psychostimulant drugs (e.g. cocaine, amphetamine) is another significant application of this class of probes. Cocaine induces neuroadaptive changes in the dopamine transporter and amphetamines are neurotoxic to dopamine neurons. Consequently, PET and SPECT imaging of the transporter can provide needed information on psychostimulant- induced addiction and toxicity in living brain and a useful strategy for investigating candidate cocaine medications. Notwithstanding these important applications, Parkinson's disease continues to be the dominant focus of dopamine transporter imaging research. Accurate imaging of dopamine nerve terminals will be useful in identifying subjects in the preclinical or early stages of the disease. This population may be candidates for emerging technologies designed to treat the disease by promoting regeneration of dopamine neurons. The effectiveness of agents that "rescue" and/or promote growth of dopamine neurons may be gauged by monitoring dopamine nerve terminals with altropane. Based on these and previous data from our laboratory a Phase I clinical trial is ongoing. Madras BK, Babich JW, Elmaleh DR, Meltzer PC, Fischman AJ. The SPECT ligand altropane effectively detects Parkinson's disease in human putamen. Soc Nucl. Med. 38 220, 1997. Madras BK, Gracz LM, Meltzer, PC, Babich J, Fischman AJ. [125I]Altropane, a SPECT imaging probe for dopamine neurons III. Human

项目成果

期刊论文数量(0)
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Bertha K Madras其他文献

Bertha K Madras的其他文献

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{{ truncateString('Bertha K Madras', 18)}}的其他基金

Long Term THC Elicits Distinct Changes in Adolescent Brain Dopamine Signaling
长期使用 THC 会引起青少年大脑多巴胺信号的明显变化
  • 批准号:
    9979805
  • 财政年份:
    2017
  • 资助金额:
    $ 3.01万
  • 项目类别:
Long Term THC Elicits Distinct Changes in Adolescent Brain Dopamine Signaling
长期使用 THC 会引起青少年大脑多巴胺信号的明显变化
  • 批准号:
    9308499
  • 财政年份:
    2017
  • 资助金额:
    $ 3.01万
  • 项目类别:
Long Term THC Elicits Distinct Changes in Adolescent Brain Dopamine Signaling
长期使用 THC 会引起青少年大脑多巴胺信号的明显变化
  • 批准号:
    10222631
  • 财政年份:
    2017
  • 资助金额:
    $ 3.01万
  • 项目类别:
A PET STUDY OF DOPAMINERGIC ACTIVITY WITH ARMODAFINIL
阿莫达非尼多巴胺能活性的宠物研究
  • 批准号:
    8357964
  • 财政年份:
    2011
  • 资助金额:
    $ 3.01万
  • 项目类别:
DOPAMINE TRANSPORTER OCCUPANCY BY NOVEL PYROVALERONE ANALOGS, A PET STUDY
新型吡咯戊酮类似物对多巴胺转运蛋白的占用,宠物研究
  • 批准号:
    8358000
  • 财政年份:
    2011
  • 资助金额:
    $ 3.01万
  • 项目类别:
ADOLESCENT AND ADULT MICE RESPOND DIFFERENTLY TO METHAMPHETAMINE
青少年和成年小鼠对甲基苯丙胺的反应不同
  • 批准号:
    8357963
  • 财政年份:
    2011
  • 资助金额:
    $ 3.01万
  • 项目类别:
MDMA ELICITS DIFFERENT BEHAVIORS, GENE EXPRESSION IN ADOLESCENT, ADULT MICE
MDMA 在青少年和成年小鼠中引发不同的行为和基因表达
  • 批准号:
    8357965
  • 财政年份:
    2011
  • 资助金额:
    $ 3.01万
  • 项目类别:
SYNTHESIS, BIOLOGICAL ASSESSMENT OF CANDIDATE MEDICATIONS FOR STIMULANT ABUSE
兴奋剂滥用候选药物的合成和生物学评估
  • 批准号:
    8358001
  • 财政年份:
    2011
  • 资助金额:
    $ 3.01万
  • 项目类别:
METHAMPHETAMINE MODULATES AXONAL GUIDANCE MOLECULES IN MOUSE HIPPOCAMPUS
甲基苯丙胺调节小鼠海马体中的轴突引导分子
  • 批准号:
    8172878
  • 财政年份:
    2010
  • 资助金额:
    $ 3.01万
  • 项目类别:
PHENETHYLAMINE (PEA) AND ATTENTION DEFICIT HYPERACTIVITY DISORDER
苯乙胺 (PEA) 和注意力缺陷多动障碍
  • 批准号:
    8172880
  • 财政年份:
    2010
  • 资助金额:
    $ 3.01万
  • 项目类别:

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