Snyder S E, Kume A, Jung Y W, Connor S E, Sherman P S, Albin R L, Wieland D M, Kilbourn M R
Division of Nuclear Medicine, University of Michigan Medical School, Ann Arbor, USA.
J Med Chem. 1995 Jul 7;38(14):2663-71. doi: 10.1021/jm00014a018.
A series of substituted 5-tert-butyl-2-phenyl-1,3-dithianes and 5-tert-butyl-2-phenyl-1,1,3,3-tetraoxo-1,3-dithianes was synthesized as ligands for the GABAA receptor complex-associated neuronal chloride ion channels. The in vitro binding affinities of these compounds for the GABA-gated chloride ion channel were determined by their ability to compete with [3H]TBOB for binding to rat brain slices. Of the eight compounds tested, trans-5-tert-butyl-2-(4-cyanophenyl)-2-methyl-1,1,3,3-tetraoxo+ ++-1,3-dithiane, 9b, trans-5-tert-butyl-2-(4-fluorophenyl)-1,1,3,3-tetraoxo-1,3-dithian e, 10, and trans-5-tert-butyl-2-(4-iodophenyl)-2-methyl-1,1,3,3-tetraoxo-1,3- dithiane, 11, showed moderately high binding affinities (Ki = 41, 180, and 105 nM, respectively). Four radioligand candidates from this series, 5-tert-butyl-2-(4-cyanophenyl)-2-[11C]methyl-1,3-dithiane, [11C]6, 5-tert-butyl-2-(4-[18F]fluorophenyl)-1,3-dithiane, [18F]7, 5-tert-butyl-2-(4-[18F]-fluorophenyl)-1,1,3,3-tetraoxo-1,3- dithiane, [18F]10, and 5-tert-butyl-2-(4-[125I]iodophenyl)-2-methyl-1,1,3,3- tetraoxo-1,3-dithiane, [125I]11, have been successfully prepared for evaluation as in vivo imaging agents useful for positron emission tomography and single photon emission computed tomography. Preliminary in vivo studies indicate significant uptake into mouse brain for [18F]7, [18F]10, and [125I]11.
合成了一系列取代的5-叔丁基-2-苯基-1,3-二硫杂环己烷和5-叔丁基-2-苯基-1,1,3,3-四氧代-1,3-二硫杂环己烷，作为γ-氨基丁酸A（GABAA）受体复合物相关神经元氯离子通道的配体。通过这些化合物与[3H]TBOB竞争结合大鼠脑片的能力，测定了它们对γ-氨基丁酸门控氯离子通道的体外结合亲和力。在测试的8种化合物中，反式-5-叔丁基-2-(4-氰基苯基)-2-甲基-1,1,3,3-四氧代-1,3-二硫杂环己烷（9b）、反式-5-叔丁基-2-(4-氟苯基)-1,1,3,3-四氧代-1,3-二硫杂环己烷（10）和反式-5-叔丁基-2-(4-碘苯基)-2-甲基-1,1,3,3-四氧代-1,3-二硫杂环己烷（11）表现出中等偏高的结合亲和力（Ki分别为41、180和105 nM）。该系列中的4种放射性配体候选物，即5-叔丁基-2-(4-氰基苯基)-2-[11C]甲基-1,3-二硫杂环己烷（[11C]6）、5-叔丁基-2-(4-[18F]氟苯基)-1,3-二硫杂环己烷（[18F]7）、5-叔丁基-2-(4-[18F]氟苯基)-1,1,3,3-四氧代-1,3-二硫杂环己烷（[18F]10）和5-叔丁基-2-(4-[125I]碘苯基)-2-甲基-1,1,3,3-四氧代-1,3-二硫杂环己烷（[125I]11）已成功制备，用于评估作为正电子发射断层扫描和单光子发射计算机断层扫描的体内成像剂。初步体内研究表明，[18F]7、[18F]10和[125I]11在小鼠脑中摄取显著。
