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完全在多巴胺上表达 神经元是生理和病理的敏感标记 帕金森氏病多巴胺神经元的变化，对 活大脑中多巴胺神经元的状态已贡献 我们对我们对自然发展的理解 疾病以及疾病严重程度与多巴胺之间的关系 多巴胺神经元的神经元耗竭成像可以鉴定人群 这将受益于旨在阻止疾病的治疗 多巴胺多巴胺的进展或促进 转运蛋白成像已扩展到其他可疑的状态 多巴胺神经元异常（E G亨廷顿氏病， 甲基苯丙胺滥用）在1989 - 90年，该实验室首先确定 有效的苯托氨烷多巴胺转运抑制剂（E CFT或WIN 35,428）作为宠物的有前途的成像剂（正电子发射 断层扫描）或SPECT（计算为Mogr Aphy的单光子发射） 转运蛋白的成像[11C] CFT（[[11C] Win 35,428）及其类似物 [123i]或[11C]易曲（Eltropane）已发展为临床试验 99mtechnetium（99mtc），是用于成像的最广泛的 但是，外围组织是技术最小的挑战，但是 基于TC的探针对大脑成像提出了重大挑战 因为金属螯合需要将同位素连接到探针上 导致探针的大脑渗透率低，我们现在报告 Novel999MTC成像剂，O-1505-T，它穿透了大脑 体外浓度相对较高，前体O-1506 显示出对多巴胺转运蛋白的高亲和力（IC50 2 05 nm） 以及低亲和力对5-羟色胺转运蛋白（IC50 497 nm）， 导致选择比> 240四个正常和两个 用MPTP处理的猴子注入了10-25个MCI O-1505T和 在2小时内获取串行SPECT图像，图像为 使用过滤后的投影算法重建，并 纹状体核比率我们在正常动物中重新计算了 O-1505T在多巴胺富含多巴胺的纹状体中的积累很快，并且 在30分钟内的积累中达到峰值水平几乎是 完全可以用未标记的CFT（1 mg/kg）取代，但不是 受类似剂量的5-羟色胺转运蛋白选择性药物的影响 纹状体：小脑比率从2 5：1至1：1下降 MPTP处理的猴子的血液清除量很快，并且 接近零60分钟的结果表明O-1505T为 优于先前报道的代理Technepine，这是合适的 用于成像多巴胺神经元的SPECT配体，因为它结合了 99mtc的1个便利标签的临界特征； 2高 纹状体：小脑比； 3多巴胺的高选择性 5-羟色胺转运蛋白； 4个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 研究提供了进一步的证据证明发展的可行性 Technetium标记的化合物S形象脑受体和 运输商出版Madras BK成像多巴胺转运蛋白A 关于多巴胺神经元神经退行性疾病的进展的窗口 1998年（J Marwah和H Teitelbaum，编辑）第1卷帕金森氏病，PP 229-253著名出版社，亚利桑那州斯科茨代尔