Elmaleh D R, Fischman A J, Shoup T M, Byon C, Hanson R N, Liang A Y, Meltzer P C, Madras B K
Department of Radiology, Massachusetts General Hospital, Boston 02114, USA.
J Nucl Med. 1996 Jul;37(7):1197-202.
Parkinson's disease is a progressive neurodegenerative disorder that is associated with the loss of nerve terminals from specific brain areas, particularly in the caudate and putamen, which contains the highest concentrations of dopamine transporter sites. Previously, we synthesized and evaluated a series of 11C-labeled 2 beta-carbomethoxy -3 beta-aryltropane (WIN 35,428; CFT) derivatives as markers for the dopamine transporter system. These ligands have high affinity and specificity for dopamine transporter sites in vitro and in vivo in laboratory animals. The goal of this study was the preparation and preliminary biological characterization of two new ligands based on the structure of WIN 35,428, the E and Z isomers of N-iodoallyl-2 beta -carbomethoxy-3 beta-(4-fluorophenyl)tropane (E and A IACFT).
E and Z IACFT were synthesized and radiolabeled with 125I. The ligands were characterized by in vitro assays of binding to dopamine and serotonin transporters and by autoradiography.
Iodine-125-IACFT was prepared in > 60% radiochemical yield, and > 98% radiochemical purity. Specific activity was 1500 Ci/mmole. In vitro, E-IACFT showed higher affinity for dopamine transporter sites than WIN 35,428 (6.6 versus 11 nM) and better selectivity than RTI-55. The Z isomer was found to have much lower affinity. One hour after an intravenous injection of 125I IACFT in monkeys, ex vivo autoradiographs of the brain revealed high concentrations of tracer in dopamine rich regions such as the caudateputamen. The striatum-to-cerebellum, striatum-to-cortex and striatum-to-thalamus ratios were 10.8, 7.2 and 8.3.
These result suggest that radiolabeled E-IACFT may be a useful radioligand for SPECT imaging of dopamine transporter sites. IACFT could prove to be extremely useful for the noninvasive evaluation of patients with early Parkinson's disease.
帕金森病是一种进行性神经退行性疾病，与特定脑区神经末梢的丧失有关，尤其是尾状核和壳核，其中多巴胺转运体部位的浓度最高。此前，我们合成并评估了一系列11C标记的2β-甲氧基羰基-3β-芳基托烷（WIN 35,428；CFT）衍生物作为多巴胺转运体系统的标记物。这些配体在体外和实验动物体内对多巴胺转运体部位具有高亲和力和特异性。本研究的目的是基于WIN 35,428的结构制备两种新的配体并进行初步生物学特性分析，即N-碘代烯丙基-2β-甲氧基羰基-3β-（4-氟苯基）托烷的E型和Z型异构体（E和A IACFT）。
合成E和Z IACFT并用125I进行放射性标记。通过与多巴胺和5-羟色胺转运体结合的体外试验及放射自显影对配体进行特性分析。
以大于60%的放射化学产率和大于98%的放射化学纯度制备了碘-125-IACFT。比活度为1500 Ci/毫摩尔。在体外，E-IACFT对多巴胺转运体部位的亲和力高于WIN 35,428（分别为6.6和11 nM），且选择性优于RTI-55。发现Z型异构体的亲和力要低得多。在猴子静脉注射125I IACFT 1小时后，脑的离体放射自显影片显示在富含多巴胺的区域如尾状核壳核中有高浓度的示踪剂。纹状体与小脑、纹状体与皮质、纹状体与丘脑的比值分别为10.8、7.2和8.3。
这些结果表明，放射性标记的E-IACFT可能是用于多巴胺转运体部位SPECT成像的有用放射性配体。IACFT可能被证明对早期帕金森病患者的无创评估极为有用。
