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志物， 帕金森氏病的治疗方法有哪些？ 多巴胺神经元在活体大脑中的状态 这对我们理解自然发展的意义重大。 疾病以及疾病严重程度与多巴胺之间的关系 多巴胺神经元成像可以识别群体 将受益于旨在阻止疾病的治疗方法 进展或促进多巴胺神经元再生多巴胺 运输成像已经扩展到其他州， 多巴胺神经元的异常（例如亨廷顿病， 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）的有前景的成像剂 断层扫描）或SPECT（单光子发射计算机断层扫描） 转运蛋白[11 C]CFT（[11 C]WIN 35，428）及其类似物的成像 [123 I]或[11 C]阿托烷已进入临床试验阶段 99 mTc（99 mTc）是最广泛用于成像的放射性核素。 因为它是最小的技术挑战。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连接到探针上 导致探头的脑部穿透率较低，我们现在报告一个 新型99 mTc显像剂O-1505-T，可穿透大脑， 在体外，前体O-1506 对多巴胺转运蛋白表现出高亲和力（IC 50 2 05 nM） 且对5-羟色胺转运蛋白的亲和力低（IC 50 497 nM）， 导致选择性比> 240，四个正态和两个正态 给MPTP处理的猴子注射10-25 mCi的O-1505 T， 在2小时内获得连续SPECT图像。 使用滤波反投影算法重建，以及 我们计算了正常动物的纹状体-小脑比率， O-1505 T在富含多巴胺的纹状体中的积累是迅速的， 在30 min内达到峰值水平， 用未标记的CFT（1 mg/kg）完全替代，但未被标记的CFT（1 mg/kg）完全替代。 受到类似剂量的血清素转运体选择性药物的影响 西酞普兰纹状体：小脑的比例从2.5：1下降到1：1， MPTP处理的猴子探针的血液清除是快速的， 结果表明，O-1505 T在60 min时接近零， 上级于先前报道的药物technepine。 用于多巴胺神经元成像的SPECT配体，因为它结合了 关键特征1 99 mTc标记容易; 2高 纹状体：小脑比率; 3对多巴胺的高选择性， 5-羟色胺转运体; 4有利的辐射剂量学; 5 药代动力学与99 mTc的物理半衰期匹配良好。 研究进一步证明了开发 锝标记的化合物s来成像脑受体， 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研究进展 1998年（J Marwah和H Teitelbaum，编辑）2001年帕金森病，pp 229-253 Prominent Press，斯科茨代尔，AZ

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