Synthesis and biological evaluation of novel 4-benzylpiperazine ligands for sigma-1 receptor imaging.
Synthesis and biological evaluation of novel 4-benzylpiperazine ligands for sigma-1 receptor imaging.
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DOI：
10.1016/j.bmc.2011.03.037
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发表时间：
2011-05
影响因子：
3.5
通讯作者：
Zi-Jing Li;Hui-Ying Ren;M. Cui;W. Deuther-Conrad;Ruikun Tang;J. Steinbach;P. Brust;Boli Liu;Hongmei Jia
中科院分区：
文献类型：
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作者：
Zi-Jing Li;Hui-Ying Ren;M. Cui;W. Deuther-Conrad;Ruikun Tang;J. Steinbach;P. Brust;Boli Liu;Hongmei Jia
我们报道了潜在的σ-1受体配体4-苄基哌嗪配体(BP-CH_3、BP-F、BP-BR、BP-I和BP-NO_2)的合成和评价。测定了具有单斜晶系P21/c空间群的BP-BR的X射线晶体结构。体外竞争结合实验表明，5种配体对σ-1受体均表现出较低的纳摩尔亲和力(Ki=0.43-0.91nM)和较高的亚型选择性(σ-2受体：Ki=0.40-61nM；Ki-σ-2/Ki-σ-1=0.52-94)。[125I]通过相应的三丁基锡前体的碘去单宁化反应，以53±10%的分离放化产率制备了BP-I(1-(1，3-benzodioxol-5-ylmethyl)-4-(4-iodobenzyl)piperazine)，提纯后的放化纯度为~99%。[125I]BP-I的logD值为2.98±0.17，在预期的脑摄取范围内。在小鼠体内的生物分布研究表明，在已知含有σ1受体的器官中，包括脑、肺、肾、心脏和脾，放射性标记物质的浓度相对较高。注射[125I]BP-I前5分钟给予氟哌啶醇可显著降低上述脏器的放射性浓度。放射性标记物质在甲状腺中的蓄积量相当低，这表明[125I]BP-I对体内去碘相对稳定。这些结果表明，在体内[125I]BP-I与σ-1受体的结合是特异的。
We report the synthesis and evaluation of 4-benzylpiperazine ligands (BP-CH3, BP-F, BP-Br, BP-I, and BP-NO2) as potential σ1receptor ligands. The X-ray crystal structure of BP-Br, which crystallized with monoclinic space groupP21/c, has been determined. In vitro competition binding assays showed that all the five ligands exhibit low nanomolar affinity for σ1receptors (Ki= 0.43–0.91 nM) and high subtype selectivity (σ2receptor:Ki= 40–61 nM;Kiσ2/Kiσ1= 52–94). [125I]BP-I (1-(1,3-benzodioxol-5-ylmethyl)-4-(4-iodobenzyl)piperazine) was prepared in 53 ± 10% isolated radiochemical yield, with radiochemical purity of >99% by HPLC analysis after purification, via iododestannylation of the corresponding tributyltin precursor. The logDvalue of [125I]BP-I was found to be 2.98 ± 0.17, which is within the range expected to give high brain uptake. Biodistribution studies in mice demonstrated relatively high concentration of radiolabeled substances in organs known to contain σ1receptors, including the brain, lung, kidney, heart, and spleen. Administration of haloperidol 5 min prior to injection of [125I]BP-I significantly reduced the concentration of radioactivity in the above-mentioned organs. The accumulation of radiolabeled substance in the thyroid was quite low suggesting that [125I]BP-I is relatively stable to in vivo deiodination. These findings suggest that the binding of [125I]BP-I to σ1receptors in vivo is specific.