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首页> 外文期刊>RSC Advances >Design, synthesis and biological evaluation of small molecule-based PET radioligands for the 5-hydroxytryptamine 7 receptor
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Design, synthesis and biological evaluation of small molecule-based PET radioligands for the 5-hydroxytryptamine 7 receptor

机译：基于小分子的PET放射性配件的设计，合成和生物学评价5-羟基对羟基胺7受体

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摘要

The 5-HT7 receptor is a recently cloned G-protein-coupled receptor (GPCR) that is important in regulating sleep, depression, and circadian rhythms. However, the potential pathophysiological roles of 5-HT7 have not been fully elucidated, and no 5-HT7 positron emission tomography (PET) radioligands are available, thus limiting imaging studies of his receptor in humans. Here, we present the radiosynthesis and biological evaluation of 5-(4-([C-11]methoxyphenyl)-1-methyl-4-nitro-1H-imidazole ([C-11]1) as a new PET ligand for 5-HT7. Three-dimensional pharmacophore evaluation and docking studies confirmed its high affinity for 5-HT7, and in vitro binding assays showed that the binding affinity was 16.8 +/- 0.9 nM. The specific activity was found to be 48 +/- 29 GBq mmol(-1) for [C-11]1 in a synthetic time of 26 +/- 3 min (n = 8), having 38 +/- 7% radiochemical yield (decay-corrected) based on [C-11]CO2. Ligand interactions with human serum albumin were studied by fluorescence quenching to obtain a Stern-Volmer plot, which showed a binding constant of 1.15 x 10(4) M-1. Whole-body biodistribution patterns were evaluated in normal mice by 1 h dynamic PET imaging; this analysis showed rapid clearance of radioactivity from the main peripheral organs, with the exception of the liver. Preliminary PET studies in rat brains showed rapid accumulation of radioactivity in the brain. The regional radioactivity reached a maximum within 0-2 min after the radioligand injection and then decreased rapidly, resulting in minimal radiation burden in the brain during the scan. In summary, this specific biaryl system has shown potential as a 5-HT7 ligand and further optimization and longitudinal studies may yield the first small molecule-based PET ligand for 5-HT7 in clinical settings.
机译：的5-HT 7受体是最近克隆的G-蛋白 - 偶联受体（GPCR），其是在调节睡眠，抑郁症，和昼夜节律重要。然而，5-HT 7的潜在病理生理作用尚未完全阐明，没有5-HT 7正电子发射断层扫描（PET）放射性可用，从而限制了他的受体显像研究人类。这里，我们提出的放射性合成和5-（4-生物评价 - （[C-11]甲氧基苯基）-1-甲基-4-硝基-1H-咪唑（[C-11] 1）作为新的PET配体5 -HT7。三维药效评价和对接研究证实了其高亲和性对5-HT 7，并在体外结合测定表明，该结合亲和力是16.8 +/- 0.9nM的。比活性被发现是48 +/- 29基于[C-11吉贝毫摩尔（-1），[C-11]中的26 +/- 3分钟（N = 8）的合成时间1，具有38 +/- 7％放射化学产率（衰变校正） ]的荧光猝灭研究了人血清白蛋白CO 2。配体的相互作用，以获得斯特恩 - 沃尔默图，其显示的结合常数1.15×10（4）M-1。全身生物分布模式通过1在正常小鼠中评价ħ动态PET成像;在大鼠脑中此分析表明放射性的快速清除来自主外周器官，与肝之外的初步PET研究表明radioactivi迅速积累TY在大脑中。区域放射性达到放射性配体注射后0-2分钟内的最大，然后迅速下降，导致在扫描期间在大脑中的最小辐射负担。总之，该特定的二芳基系统显示出潜在的作为5-HT 7配体和进一步的优化和纵向研究可以产生第一基于小分子的PET配体对5-HT7在临床环境中。

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  • 来源
    《RSC Advances》 |2015年第25期|共8页
  • 作者

    Tiwari A. K.; Yui J.; Pooja; Aggarwal S.; Yamasaki T.; Xie L.; Chadha N.; Zhang Y.; Fujinaga M.; Shimoda Y.; Kumata K.; Mishra A. K.; Ogawa M.; Zhang M. -R.;

  • 作者单位

    Inst Nucl Med &

    Allied Sci Div Cyclotron &

    Radiopharmaceut Sci Delhi 110054 India;

    Natl Inst Radiol Sci Mol Imaging Ctr Inage Ku Chiba 2638555 Japan;

    Inst Nucl Med &

    Allied Sci Div Cyclotron &

    Radiopharmaceut Sci Delhi 110054 India;

    Inst Nucl Med &

    Allied Sci Div Cyclotron &

    Radiopharmaceut Sci Delhi 110054 India;

    Natl Inst Radiol Sci Mol Imaging Ctr Inage Ku Chiba 2638555 Japan;

    Natl Inst Radiol Sci Mol Imaging Ctr Inage Ku Chiba 2638555 Japan;

    Inst Nucl Med &

    Allied Sci Div Cyclotron &

    Radiopharmaceut Sci Delhi 110054 India;

    Natl Inst Radiol Sci Mol Imaging Ctr Inage Ku Chiba 2638555 Japan;

    Natl Inst Radiol Sci Mol Imaging Ctr Inage Ku Chiba 2638555 Japan;

    Natl Inst Radiol Sci Mol Imaging Ctr Inage Ku Chiba 2638555 Japan;

    Natl Inst Radiol Sci Mol Imaging Ctr Inage Ku Chiba 2638555 Japan;

    Inst Nucl Med &

    Allied Sci Div Cyclotron &

    Radiopharmaceut Sci Delhi 110054 India;

    SHI Accelerator Serv Co Ltd Shinagawa Ku Tokyo 1418686 Japan;

    Natl Inst Radiol Sci Mol Imaging Ctr Inage Ku Chiba 2638555 Japan;

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