ALTROPANE, SPECT OR PET IMAGING PROBE FOR DOPAMINE NEURONS I & IN PRIMATE BRAIN

越来越多的证据表明多巴胺转运体是一种 多巴胺神经元病理变化的重要标志， 包括帕金森氏症、衰老和药物滥用。强有力的 苯基托烷系列的多巴胺转运抑制剂(例如Win 35,428或CFT)是最有效的PET候选对象 (正电子发射断层扫描)或SPECT(单光子发射 计算机断层扫描)活体多巴胺转运体的成像 大脑。该项目的目标是调查 Win 35,428的N-碘烯丙基衍生物--阿托品 (IACFT：E-N-碘烯丙基-2-甲氧基-3-(4-氟苯基)托烷)， 显示适合作为SPECT进行评估的体外特性 成像剂。食蟹猴纹状体内， 大脑中含有最高水平多巴胺的区域， 未标记的E-异构体(IC_(50)6.62 Q_(0.78)nM)比 Z-异构体(IC50 52.6 Q 0.3 nm)，表现出相对较高的 多巴胺：5-羟色胺转运体选择性(28倍)。在无线电标记中 形式，[125I]阿托品与纹状体中的部位结合 高亲和力(Kd 5.33 Q 0.55 NM)和具有位置密度(Bmax 301 Pmol/g原始湿组织重量)在密度范围内 之前报道过纹状体中的多巴胺转运蛋白。 饱和实验表明，[125I]阿托品可识别 单个亲和结合部位，而不是两个结合部位 用[~3H]Win 35,428或 其他脑显像剂(例如[125I]RTI-55(-CIT)或 [125I]RTI-121)。阿托品的这种意想不到的性质是 是有利的，因为单个亲和位点的检测允许 在体外定量转运蛋白密度的相对容易 或者在活体内。药物抑制[125I]阿托品与[125I]结合 与他们的等级顺序密切相关的效力 抑制[~3H]Win 35,428结合(R2 0.99；p&lt；0.0001)和 阻碍了多巴胺的运输。这些结果表明，结合 多巴胺转运蛋白上的结构域可以容纳大量的 苯基托烷的胺氮区域。的选择性 阿托品对多巴胺的5-羟色胺转运体也是一个 阿托洛烷的良好性能是因为存在 灵长类纹状体5-羟色胺转运体的可能性 5-羟色胺纤维在纹状体发芽， 腹侧中脑移植的5-羟色胺神经元寄主纹状体， 纹状体对比度增强。基于高亲和力和 阿托品对多巴胺转运体的选择性，阿托品是一种 多巴胺状态成像和监测的候选标记物 转运蛋白和相关的多巴胺神经元。马德拉斯·BK， 首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细内容 [125I]Altroane，一种SPECT成像探针

Increasing evidence suggests that the dopamine transporter is an important marker for pathological changes in dopamine neurons, including Parkinson's disease, aging and substance abuse. Potent dopamine transport inhibitors of the phenyltropane series (e.g. WIN 35,428 or CFT) are among the most effective candidates for PET (positron emission tomography) or SPECT (single photon emission computed tomography) imaging of the dopamine transporter in living brain. The goals of this project were to investigate whether altropane, an N-iodoallyl derivative of WIN 35,428 (IACFT:E-N-iodoallyl-2 -carbomethoxy-3 -(4-fluorophenyl)tropane), displays in vitro properties suitable for evaluation as a SPECT imaging agent. In cynomolgus monkey (Macaca fascicularis) striatum, the region containing the highest levels of dopamine in brain, the unlabeled E- isomer (IC50 6.62 q 0.78 nM) was more potent than the Z-isomer (IC50 52.6 q 0.3 nM) and displayed a relatively high dopamine:serotonin transporter selectivity (28-fold). In radiolabeled form, [125I]altropane bound to sites in the striatum with a single high affinity (KD 5.33 q 0.55 nM) and with a site density (BMAX 301 pmol/g original wet tissue weight) that was within the density range reported previously for the dopamine transporter in striatum. Saturation experiments revealed that [125I]altropane recognized a single affinity binding site, in contrast to the two binding components characteristically detected with [3H]WIN 35,428 or with other brain imaging agents, (e.g. [125I]RTI-55 ( -CIT) or [125I]RTI-121). This unanticipated property of altropane is advantageous because detection of a single affinity site allows for relative ease in quantifying the density of the transporter in vitro or in vivo. Drugs inhibited [125I]altropane binding with a rank order of potency that corresponded closely to their rank order for inhibiting [3H]WIN 35,428 binding (r2 0.99; p < 0.0001) and for blocking dopamine transport. These results indicate that the binding domain on the dopamine transporter can accommodate large groups in the region of the amine nitrogen of phenyltropanes. The selectivity of altropane for the dopamine over the serotonin transporter is also a favorable property of altropane because of the presence of the serotonin transporter in primate striatum, the possibility of serotonin fiber sprouting in the striatum, hyperinnervation of the host striatum by serotonin neurons from ventral mesencephalon grafts, and increased striatal contrast. Based on the high affinity and selectivity of altropane for the dopamine transporter, altropane is a candidate marker for imaging and monitoring the status of the dopamine transporter, and associated dopamine neurons in brain. Madras BK, Meltzer PC, Liang AY, Hanson R, Elmaleh DE, Babich J, Fischman AJ. [125I]Altropane, a SPECT Imaging Probe for