Synthesis and in vitro evaluation of iodinated derivatives of piperazine as a new ligand for sigma receptor imaging by single photon emission computed tomography.
Synthesis and in vitro evaluation of iodinated derivatives of piperazine as a new ligand for sigma receptor imaging by single photon emission computed tomography.
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DOI：
10.1248/cpb.54.470
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发表时间：
2006-04
影响因子：
1.7
通讯作者：
M. Hirata;Tetsuya Mori;Seigo Soga;T. Umeda;Y. Ohmomo
中科院分区：
文献类型：
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作者：
M. Hirata;Tetsuya Mori;Seigo Soga;T. Umeda;Y. Ohmomo
合成了一系列新的1-[2-（3，4-二甲氧基苯基）乙基]-4-（3-苯丙基）哌嗪（SA 4503）的放射性碘标记类似物，并通过单光子发射计算机断层扫描（SPECT）评价了其作为脑sigma-1受体显像配体的潜力。从哌嗪以高产率制备了SA 4503的碘化类似物（4a-c）。使用[3 H] DTG（sigma-1，2）、[3 H]（+）-喷他佐辛（sigma-1）和[3 H] DTG在存在碳五戊烷（sigma-2）作为sigma受体选择性放射性配体的情况下进行的体外竞争结合研究显示，碘化类似物4a-c对sigma受体具有高亲和力（IC 50：4a=7.1，4 b =31.0和4c=77.3 nM）。特别是，在苯环邻位带有碘的4a的亲和力是SA 4503的4.4倍，是氟哌啶醇的3倍。间碘类似物4 b与先导化合物SA 4503相同。以相应的三丁基锡前体为原料，通过碘脱锡反应，在不添加载体的情况下高产率合成了放射性碘标记衍生物[125 I] 4a、4 b。[125 I] 4a，4 b在大鼠脑细胞膜上的结合已被表征。这些化合物被表明以高亲和力（4a：Kd=1.86+/-0.34 nM，Bmax=205+/-28.9 fmol/mg蛋白，4 b：Kd=3.30+/-0.51 nM，Bmax=231.5+/-13.8 fmol/mg蛋白）与σ受体结合的单一群体。体外阻断研究证实，4a、4 b的特异性高。这些结果表明，放射性碘标记的4a和4 b是有前途的σ受体成像配体，用于进一步的体内研究。
A new series of radioiodinated analogues of 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503) was synthesized and evaluated as a potential brain sigma-1 receptor imaging ligands by single photon emission computed tomography (SPECT). Iodinated analogues of SA4503 (4a-c) were prepared from piperazine in a high yield. The in vitro competition binding studies using [3H] DTG (sigma-1, 2), [3H] (+)-pentazocine (sigma-1), and [3H] DTG in the presence of carbetapentane (sigma-2) as sigma receptor selective radioligands were revealed that iodinated analogues 4a-c possess high affinities to sigma receptors (IC50: 4a=7.1, 4b=31.0, and 4c=77.3 nM). In particular, the affinity of 4a, bearing iodine at ortho position on the phenyl ring, was 4.4 times greater than SA4503, and 3 times greater than that of haloperidol. The meta-iodo analogue 4b was the same to SA4503, the lead compound. The radioiodinated derivatives, [125I] 4a, 4b were synthesized no-carrier-added from the corresponding tributyltin precursors by the iododestannylation reaction with high yields. The binding of [125I] 4a, 4b have been characterized in the rat brain membranes. These compounds were indicated single population binding to sigma receptor with high affinity (4a: Kd=1.86+/-0.34 nM, Bmax=205+/-28.9 fmol/mg protein, 4b: Kd=3.30+/-0.51 nM, Bmax=231.5+/-13.8 fmol/mg protein). In vitro blocking studies were confirmed that the high specificity of 4a, 4b. These results suggest that radioiodinated 4a and 4b are promising sigma receptors imaging ligand for pursuing further in vivo studies.