4-Iodotomoxetine: a novel ligand for serotonin uptake sites.
4-Iodotomoxetine: a novel ligand for serotonin uptake sites.
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4-碘托莫西汀：血清素吸收位点的新型配体。
DOI：
10.1016/0024-3205(92)90002-7
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发表时间：
1992
期刊：
影响因子：
6.1
通讯作者：
Kung,H
中科院分区：
文献类型：
--
作者：
Kung,MP;Chumpradit,S;Billings,J;Kung,H
托莫西汀类似物，R-4-碘托莫西汀，结合素体外高亲和力地结合到大鼠皮质膜的单一部位(Kd=0.03±0.01 nM，n=4)，并可被选择性5-羟色胺再摄取位点抑制剂帕罗西汀阻断。平衡状态下的[125L]R-4-碘托莫西汀的结合是可饱和的，并且依赖于温度和Na+。已知的5-羟色胺摄取抑制剂[~(125)L]R-4-碘托莫西汀结合位点数(Bmax=356±20fmol/mg蛋白)与[~3H]西酞普兰(329±30fmol/mg蛋白)相似。几种5-羟色胺摄取阻滞剂选择性地抑制[125I]R-4-碘托莫西汀的结合，且不同药物对[125I]R-4-碘托莫西汀体外结合的抑制作用与[~3H]西普兰之间有很好的相关性。此外，与假手术对照组相比，神经毒素对氯苯丙胺破坏单胺神经元，包括5-羟色胺能神经元系统，导致[125L]R-4-碘托莫西汀结合减少90%。这些结果表明，~(125)I-R-4-碘托莫西汀标记的结合部位与神经元摄取5-羟色胺的部位有关。然而，Vivoandex的活体结果并没有显示出与5-羟色胺摄取部位分布相对应的区域定位。这种非特异性吸收可能与该化合物的高亲油性有关(在pH=7时，辛醇-缓冲液分配系数=1100−1400)。尽管[125l]R-4-碘托莫西汀的活体性质使其不太可能成为SPECT绘制5-羟色胺摄取部位图的候选物质，但它的高亲和力和选择性应使其成为5-羟色胺摄取部位体外研究的有用工具。
The tomoxetine analog, R-4-iodotomoxetine, bindsin vitroto a single site of rat cortical membranes with high affinity (Kd=0.03±0.01 nM, n=4) and can be blocked by a selective serotonin reuptake site inhibitor, paroxetine. The [125l]R-4-iodotomoxetine binding at equilibrium is saturable and is temperature- and Na+-dependent. The number of specific [125l]R-4- iodotomoxetine binding sites (Bmax=356±20 fmol/mg protein) is similar to that of [3H]citalopram (329±30 fmol/mg protein), a known serotonin uptake inhibitor. The binding of [125l]R-4-iodotomoxetine is selectively inhibited by several serotonin uptake blockers, and a good correlation is demonstrated between the potency of various drugs to inhibitin vitrobinding of [125l]R-4- iodotomoxetine and [3H]citalopram. In addition, lesions performed with the neurotoxin p-chloroamphetamine, which destroys monoamine neurons, including serotonergic neuronal system, result in a 90% reduction of [125l]R-4- iodotomoxetine binding when compared to sham controls. These results indicate that the binding sites labeled by [125l]R-4-iodotomoxetine are associated with the neuronal serotonin uptake sites. However, thein vivoandex vivoresults do not show regional localization corresponding to the distribution of serotonin uptake sites. The nonspecific uptake may be related to this compound's high lipophilicity (octanol-buffer partition coeffient = 1100−1400 at pH 7). Although thein vivoproperties of [125l]R-4- iodotomoxetine make it an unlikely candidate for mapping serotonin uptake sites with SPECT, the high affinity and selectivity should make it a useful tool forin vitrostudies of the serotonin uptake sites.