Madras B K, Gracz L M, Fahey M A, Elmaleh D, Meltzer P C, Liang A Y, Stopa E G, Babich J, Fischman A J
Department of Psychiatry, Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts 01772-9102, USA.
Synapse. 1998 Jun;29(2):116-27. doi: 10.1002/(SICI)1098-2396(199806)29:2<116::AID-SYN3>3.0.CO;2-A.
Increasing evidence suggests that the dopamine transporter is situated almost exclusively on dopamine neurons. Accordingly, it is an valuable marker for Parkinson's disease and other pathological states of dopamine neurons. We previously demonstrated that the potent dopamine transport inhibitor [125I]altropane (IACFT:E-N-iodoallyl-2beta-carbomethoxy-3beta-(4-fluor ophenyl)tropane) is a high affinity selective probe for the dopamine transporter in monkey brain and an effective SPECT imaging agent in nonhuman primate brain. We now report the binding properties of [125I]altropane in postmortem tissue of normal human brain and compare the findings to Parkinson's diseased brain. In homogenates of human brain putamen, [125I]altropane bound with high affinity (KD: 4.96 +/- 0.38 nM, n = 4) and site density (BMAX: 212 +/- 41.1 pmol/g original wet tissue weight) well within the density range reported previously for the dopamine transporter in this brain region. Drugs inhibited [125I]altropane binding with a rank order of potency that corresponded closely to their rank order for blocking dopamine transport (r 0.98, P < 0.001). In postmortem Parkinson's diseased brain, bound [125I]altropane (1 nM) was markedly reduced (89%, 99% in putamen, depending on measures of nonspecific binding) compared with normal aged-matched controls (normal putamen: 49.2 +/- 8.1 pmol/g; Parkinson's diseased putamen: 0.48 +/- 0.33 pmol/g; n = 4). In vitro autoradiography, conducted in tissue sections at a single plane of the basal ganglia, revealed high levels of [125I]altropane binding the caudate nucleus and putamen, but lower levels (73% of the caudate-putamen) in the nucleus accumbens (n = 7). In Parkinson's diseased brains (n = 4), [125I]altropane binding was 13% of the levels detected in normal putamen, 17% of normal values in the caudate nucleus, and 25% of normal levels in nucleus accumbens. The association of [125I]altropane to the dopamine transporter in human postmortem tissue, the marked reduction of [125I]altropane binding in Parkinson's diseased brains, its rapid entry into brain and highly localized distribution in dopamine-rich brain regions, support its use as a probe for monitoring the dopamine transporter in vitro and in vivo by SPECT imaging.
越来越多的证据表明，多巴胺转运体几乎只存在于多巴胺能神经元上。因此，它是帕金森病和多巴胺能神经元其他病理状态的一个有价值的标志物。我们之前证明，强效多巴胺转运抑制剂[125I]阿曲泛（IACFT：E-N-碘烯丙基-2β-甲氧羰基-3β-（4-氟苯基）托烷）是猴脑中多巴胺转运体的高亲和力选择性探针，也是非人灵长类动物脑中有效的单光子发射计算机断层扫描（SPECT）显像剂。我们现在报告[125I]阿曲泛在正常人类脑死后组织中的结合特性，并将结果与帕金森病脑进行比较。在人脑壳核匀浆中，[125I]阿曲泛以高亲和力结合（解离常数KD：4.96±0.38 nM，n = 4），位点密度（最大结合量BMAX：212±41.1 pmol/g原始湿组织重量）完全在该脑区先前报道的多巴胺转运体密度范围内。药物抑制[125I]阿曲泛结合的效力顺序与它们阻断多巴胺转运的顺序密切相关（r = 0.98，P < 0.001）。在帕金森病死后脑中，与年龄匹配的正常对照相比，结合的[125I]阿曲泛（1 nM）明显减少（壳核中减少89%，99%，取决于非特异性结合的测量方法）（正常壳核：49.2±8.1 pmol/g；帕金森病壳核：0.48±0.33 pmol/g；n = 4）。在基底神经节单个平面的组织切片上进行的体外放射自显影显示，[125I]阿曲泛在尾状核和壳核中有高水平结合，但在伏隔核中的水平较低（为尾状核-壳核的73%）（n = 7）。在帕金森病脑中（n = 4），[125I]阿曲泛结合量为正常壳核中检测水平的13%，尾状核中正常水平的17%，伏隔核中正常水平的25%。[125I]阿曲泛与人脑死后组织中多巴胺转运体的结合、帕金森病脑中[125I]阿曲泛结合的显著减少、其快速进入脑内以及在富含多巴胺的脑区高度局部化分布，支持其作为通过SPECT成像在体外和体内监测多巴胺转运体的探针。
