Lee L C, Vander Borght T, Sherman P S, Frey K A, Kilbourn M R
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109, USA.
J Med Chem. 1996 Jan 5;39(1):191-6. doi: 10.1021/jm950117b.
Tetrabenazine is a high-affinity inhibitor of the vesicular monoamine transporter in mammalian brain. As part of a program to develop in vivo imaging agents for these transporters in human brain, a series of 2-alkylated dihydrotetrabenazine ligands was synthesized and evaluated in vitro and in vivo for binding to the brain vesicular monoamine transporter. Additions of organometallic reagents to tetrabenazine produced 2-methyl, 2-ethyl, 2-n-propyl, 2-isopropyl, and 2-isobutyl derivatives of dihydrotetrabenazine. The stereochemistry and conformation of the addition products were thoroughly verified by two-dimensional NMR techniques. All of these alkyl derivatives displayed in vitro affinity for the vesicular monoamine transporter binding site in rat brain using competitive assays with the radioligand [3H]methoxytetrabenazine. Except for the isopropyl derivative, all compounds when tested at 10 mg/kg iv showed an ability to inhibit in vivo accumulation of the radioligand [11C]methoxytetrabenazine in the mouse brain striatum. Derivatives with small alkyl groups (methyl, ethyl) were more effective than those with large groups (propyl, isobutyl). These studies suggest that large groups in the 2-position of the benzisoquinoline structure will significantly diminish both in vitro and in vivo binding of these compounds to the vesicular monoamine transporter.
丁苯那嗪是哺乳动物脑中囊泡单胺转运体的高亲和力抑制剂。作为开发用于人脑这些转运体的体内成像剂计划的一部分，合成了一系列2-烷基化二氢丁苯那嗪配体，并在体外和体内评估了它们与脑囊泡单胺转运体的结合情况。将有机金属试剂添加到丁苯那嗪中，生成了二氢丁苯那嗪的2-甲基、2-乙基、2-正丙基、2-异丙基和2-异丁基衍生物。通过二维核磁共振技术彻底验证了加成产物的立体化学和构象。使用放射性配体[3H]甲氧基丁苯那嗪的竞争性测定法，所有这些烷基衍生物在体外对大鼠脑囊泡单胺转运体结合位点均显示出亲和力。除异丙基衍生物外，所有化合物静脉注射10mg/kg时均显示出抑制放射性配体[11C]甲氧基丁苯那嗪在小鼠脑纹状体中体内蓄积的能力。具有小烷基（甲基、乙基）的衍生物比具有大烷基（丙基、异丁基）的衍生物更有效。这些研究表明，苯并异喹啉结构中2-位的大基团将显著降低这些化合物在体外和体内与囊泡单胺转运体的结合。
