Goodman M M, Kung M P, Kabalka G W, Kung H F, Switzer R
Department of Radiology, University of Tennessee Medical Center at Knoxville 37920.
J Med Chem. 1994 May 13;37(10):1535-42. doi: 10.1021/jm00036a020.
Methods have been developed for the preparation of radioiodinated N-substituted 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropanes. The syntheses, physical properties, radiolabeling, and characterization of the pharmacological properties of N-(3(Z)-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (12) and N-(3(E)-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (13) are described. 2 beta-Carbomethoxy-3 beta-(p-substituted-phenyl)tropanes are potent ligands for the dopamine transporter. The radioiodinated derivatives are of interest because of the high uptake and prolonged striatal retention that may result from specific binding to low-capacity, high-affinity, dopamine reuptake sites. Radioiodine was introduced into the 3Z and 3E-position of N-(3-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane by iododemetalation of the corresponding 3-(tri-n-butylstannyl) derivatives. Competition binding data of various dopamine reuptake ligands with rat striatal tissue preparation for either [125I]-12 or [125I]-13 exhibited the following order of potency: E-13 > Z-12 > GBR 12909 >> mazindol >>> (-)-cocaine. Tissue distribution studies in rats showed that the E-13 was the best analogue. E-13 showed high striatal uptake (60 min, 1.23% dose/g; 120 min, 0.61% dose/g) and high striatal to cerebellum ratios (60 min, 15.9/1; 120 min, 16.5/1). These studies indicate that iodine-123-labeled E-13 is a potentially useful agent for imaging the dopamine reuptake sites by single-photon-emission computerized tomography.
已开发出制备放射性碘化 N-取代的 2β-甲氧羰基-3β-(4-氯苯基)托烷的方法。描述了 N-(3(Z)-碘代丙烯-1-基)-2β-甲氧羰基-3β-(4-氯苯基)托烷(12)和 N-(3(E)-碘代丙烯-1-基)-2β-甲氧羰基-3β-(4-氯苯基)托烷(13)的合成、物理性质、放射性标记以及药理性质的表征。2β-甲氧羰基-3β-(对取代苯基)托烷是多巴胺转运体的有效配体。放射性碘化衍生物因其可能通过与低容量、高亲和力的多巴胺再摄取位点特异性结合而导致的高摄取和纹状体长时间滞留而受到关注。通过相应的 3-(三正丁基锡基)衍生物的碘脱金属反应，将放射性碘引入 N-(3-碘代丙烯-1-基)-2β-甲氧羰基-3β-(4-氯苯基)托烷的 3Z 和 3E 位。各种多巴胺再摄取配体与大鼠纹状体组织制剂对[125I]-12 或[125I]-13 的竞争结合数据显示出以下效力顺序：E-13 > Z-12 > GBR 12909 >> 吗茚酮 >>> (-)-可卡因。大鼠体内组织分布研究表明 E-13 是最佳类似物。E-13 显示出高纹状体摄取(60 分钟，1.23%剂量/克；120 分钟，0.61%剂量/克)和高纹状体与小脑比值(60 分钟，15.9/1；120 分钟，16.5/1)。这些研究表明，碘-123 标记的 E-13 是一种通过单光子发射计算机断层扫描成像多巴胺再摄取位点的潜在有用试剂。
