LABEL DOPAMINE NEURONS IN BRAINS OF NORMAL & MPTP TREATED MONKEYS

多巴胺转运蛋白，几乎只在多巴胺上表达 神经元，是生理和病理的敏感标记物 帕金森氏病患者多巴胺神经元的变化 活脑中多巴胺神经元的地位起到了一定作用 对我们理解生物多样性的自然发展具有重要意义 疾病及其严重程度与多巴胺的关系 多巴胺神经元耗竭成像可识别群体 这将受益于旨在遏制疾病的治疗 促进或促进多巴胺神经元再生 传送器成像已经扩展到其他州，怀疑 多巴胺神经元的异常(如亨廷顿病， 滥用甲基苯丙胺)在1989-90年间，该实验室首次发现 强效苯基托烷多巴胺转运抑制剂(如CFT或WIN 35,428)作为有前途的正电子发射(PET)显像剂 断层扫描)或SPECT(单光子发射计算) 转运蛋白[11C]CFT([11C]Win 35,428)及其类似物的成像 [123I]或[11C]阿托品已进入临床试验 ~(99m)Tc是目前应用最广泛的放射性核素 然而，由于它是最小的技术挑战， 基于TC的探针对脑成像提出了重大挑战 因为金属络合物需要将同位素连接到探针上 导致探头脑渗透率低的结果我们现在报告一种 新型99mTc显像剂O-1505-T 在体外浓度相对较高的前体O-1506 显示对多巴胺转运体的高亲和力(IC50 2 05 NM) 对5-羟色胺转运体的亲和力低(IC50 497 NM)， 导致选择性比&gt；240四个正常和两个 给MPTP处理的猴子注射10-25mCI的O-1505T和 连续采集SPECT图像超过2小时。 使用滤波反投影算法进行重建 我们在正常动物身上计算了纹状体和小脑的比例， O-1505T在富含多巴胺的纹状体中积聚迅速， 峰值水平在30分钟内达到，累积几乎 使用未标记的CFT(1毫克/公斤)可完全置换，但不能 受到类似剂量的5-羟色胺转运体选择性药物的影响 西酞普兰的纹状体与小脑比例从2 5：1降至1：1。 经MPTP处理的猕猴血液清除探针快速、稳定 结果表明，O-1505T在60min时接近于零 它优于以前报道的药物替克奈平，是一种合适的 用于多巴胺神经元成像的SPECT配体，因为它结合了 ~(99m)Tc-1简易标记的临界特性 纹状体：小脑比率；3多巴胺的高选择性超过 5-羟色胺转运体；4个有利的辐射剂量测定；5 药物动力学与99mTc This的物理半衰期很好地匹配 研究提供了进一步的证据，证明开发 氚标记化合物S对脑内受体和脑组织的成像 转运体出版物Madras BK成像多巴胺转运体a 多巴胺神经元在神经退行性疾病中的研究进展 1998(J Marwah和H Teitelbaum主编)第一卷帕金森病，pp 229-253 AZ斯科茨代尔卓越出版社

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