LABEL DOPAMINE NEURONS IN BRAINS OF NORMAL & MPTP TREATED MONKEYS

标记正常人大脑中的多巴胺神经元

• 批准号: 6591305
• 负责人: Bertha K Madras
• 金额: $ 11.11万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6591305
• 关键词: Mammalia; aging; animal tissue; bioimaging /biomedical imaging; drug adverse effect; nervous system; pharmacology; radiology; spectrometry; substance abuse related disorder; technology /technique

The dopamine transporter, expressed almost exclusively on dopamine neurons, is a sensitive marker for physiological and pathological changes in dopamine neurons In Parkinson's disease, a view of the status of dopamine neurons in living brain has contributed significantly to our understanding of the natural progression of the disease and the relationship between disease severity and dopamine neuron depletion Imaging of dopamine neurons can identify populations that will benefit from treatments designed to arrest disease progression or promote regeneration of dopamine neurons Dopamine transporter imaging has extended to other states with suspected abnormalities in dopamine neurons (e g Huntington's disease, methamphetamine abuse) In 1989-90, this laboratory first identified potent phenyltropane dopamine transport inhibitors (e g CFT or WIN 35,428) as promising imaging agents for PET (positron emission tomography) or SPECT (single photon emission computed to mogr aphy) imaging of the transporter [11C]CFT ([11C]WIN 35,428) and its analog [123I]or [11C]altropane have progressed to clinical trials 99mTechnetium (99mTc), is the most widely used for imaging of peripheral tissues as it is the least technical challenge However, Tc-based probes present a significant challenge for brain imaging because the metal chelate needed to attach the isotope to a probe results in low brain penetration of the probe We now report a novel99mTc imaging agent, O-1505-T which penetrates the brain at relatively high concentrations In vitro, the precursor O-1506 displayed high affinity for the dopamine transporter (IC50 2 05 nM) and low affinity for the serotonin transporter (IC50 497 nM), resulting in a selectivity ratio > 240 Four normal and two MPTP-treated monkeys were injected with 10-25 mCi of O-1505T and serial SPECT images were acquired over 2 h The images were reconstructed using a filtered back projection algorithm and striatal-cerebellar ratios we re calculated In normal animals, accumulation of O-1505T in the dopamine-rich striatum was rapid and peak levels were achieved within 30 min Accumulation was nearly completely displaceable with unlabeled CFT (1 mg/kg) but was not affected by a similar dose of the serotonin transporter-selective drug citalopram The striatal:cerebellar ratio fell from 2 5:1 to 1:1 in MPTP-treated monkeys Blood clearance of the probe was rapid and approached zero by 60 min The results demonstrate that O-1505T is superior to the previously reported agent technepine It is a suitable SPECT ligand for imaging dopamine neurons because it combines the critical characteristics of 1 Facile labeling with 99mTc; 2 High striatal:cerebellar ratio; 3 High selectivity for dopamine over serotonin transporters; 4 Favorable radiation dosimetry; 5 Pharmacokinetics well matched to the physical half-life of 99mTc This study provides further evidence of the feasibility of developing technetium-labeled compound s to image brain receptors and transporters PUBLICATION Madras BK Imaging the dopamine transporter a window on dopamine neurons Advances in Neurodegenerative Disorders 1998 (J Marwah and H Teitelbaum, eds ) Vol 1 Parkinson's disease, pp 229- 253 Prominent Press, Scottsdale, AZ

多巴胺转运蛋白，几乎仅在多巴胺上表达 神经元，是生理和病理的敏感标志物 帕金森病中多巴胺神经元的变化 活体大脑中多巴胺神经元的状态做出了贡献 对我们对自然进​​程的理解具有重要意义 疾病以及疾病严重程度与多巴胺之间的关系 神经元耗竭 多巴胺神经元成像可以识别群体 将从旨在阻止疾病的治疗中受益 多巴胺神经元的进展或促进再生 转运蛋白成像已扩展到其他疑似病例的州 多巴胺神经元异常（例如亨廷顿病， 甲基苯丙胺滥用）在 1989-90 年，该实验室首次发现 有效的苯托烷多巴胺转运抑制剂（例如 CFT 或 WIN 35,428）作为 PET（正电子发射 断层扫描）或 SPECT（单光子发射计算成像） 转运蛋白 [11C]CFT ([11C]WIN 35,428) 及其类似物的成像 [123I]或[11C]阿托烷已进入临床试验阶段 99m锝 (99mTc) 是最广泛用于成像的 外围组织，因为它是技术挑战最小的然而， 基于 Tc 的探针对脑成像提出了重大挑战 因为金属螯合物需要将同位素附着到探针上 导致探针的大脑穿透力低我们现在报告 新型 99mTc 显像剂 O-1505-T 可穿透大脑 体外浓度相对较高，前体 O-1506 对多巴胺转运蛋白表现出高亲和力 (IC50 2 05 nM) 对血清素转运蛋白的亲和力低 (IC50 497 nM)， 导致选择性比 > 240 四个正常和两个 MPTP 处理的猴子注射 10-25 mCi 的 O-1505T 和 连续 SPECT 图像在 2 小时内获得 使用滤波反投影算法重建并且 我们重新计算了正常动物的纹状体-小脑比率， O-1505T 在富含多巴胺的纹状体中快速积累 30分钟内达到峰值 累积量接近 可以用未标记的 CFT (1 mg/kg) 完全替代，但不能 受到类似剂量的血清素转运蛋白选择性药物的影响 西酞普兰纹状体与小脑的比例从 2·5:1 降至 1:1 MPTP 处理的猴子 探针的血液清除速度很快，并且 60 分钟接近零 结果表明 O-1505T 是 优于先前报道的药剂technepine，它是一种合适的 用于成像多巴胺神经元的 SPECT 配体，因为它结合了 1 的关键特性 使用 99mTc 轻松标记； 2 高 纹状体：小脑比率； 3 对多巴胺的高选择性 血清素转运蛋白； 4 有利的辐射剂量测定； 5 药代动力学与 99mTc 的物理半衰期非常匹配 研究进一步证明了开发的可行性 锝标记的化合物可对大脑受体进行成像 转运蛋白 出版物 Madras BK 成像多巴胺转运蛋白 a 多巴胺神经元的窗口神经退行性疾病的进展 1998 年（J Marwah 和 H Teitelbaum，编辑）第 1 卷帕金森氏病，第 10 页 229- 253 Prominent Press，亚利桑那州斯科茨代尔