New 99mTc(CO)3(NNO) complexes in the development of 5-HT1A receptor imaging agents
New 99mTc(CO)3(NNO) complexes in the development of 5-HT1A receptor imaging agents
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DOI：
10.1524/ract.2011.1835
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发表时间：
2011-01-01
影响因子：
1.8
通讯作者：
Papadopoulos, M.
中科院分区：
文献类型：
--
作者：
Chiotellis, A.;Tsoukalas, C.;Papadopoulos, M.
在这项工作中，我们报道了两种新的中性三羰基面-M(CO)(3)(NNO) （M = Re, Tc-99m）衍生物WAY-100635的合成、表征和生物学评价，作为5-HT1A受体体内成像的潜在Tc-99m药物。新的药效基团NNO配体是基于吡咯胺N，N-二乙酸（PADA）配体，它们的合成是通过PADA酸酐实现的，因此表明了我们实验室开发的这种合成方法在PADA分子中掺入生物活性胺和开发靶向放射性药物方面的适用性。以[NEt4](2)[Re(CO)(3)Br-3]为前驱体合成了铼配合物，并用元素分析和光谱方法对其进行了表征。用[Tc-99m(CO)(3)(H2O)(3)]（+）前驱体定量制备了类似的锝-99m配合物，并用铼配合物对其结构进行了确证。Tc配合物的亲脂性在通常允许物质穿过血脑屏障的范围内。竞争结合试验显示，5-HT1A受体具有中等亲和力，IC50值在纳摩尔范围（30和116 nM）。在健康动物中的生物分布特点是初始血液和肝脏摄取高，血液和组织净化快，排泄主要通过肝胆系统进行。没有一种新的复合物显示出明显的脑吸收，这表明化合物通过血脑屏障的能力不仅仅是由电荷、亲脂性和大小决定的。
In this work we report the synthesis, characterization and biological evaluation of two new neutral tricarbonyl fac-M(CO)(3)(NNO) (M = Re, Tc-99m) derivatives of WAY-100635 as potential Tc-99m agents for the in vivo imaging of 5-HT1A receptors. The new pharmacophore NNO ligands are based on the picolylamine N,N-diacetic acid (PADA) ligand and their synthesis was achieved through the PADA anhydride, showing thus the applicability of this synthetic approach, developed in our laboratory, for the incorporation of bioactive amines in the PADA molecule and the development of target specific radiopharmaceuticals. The rhenium complexes were synthesized using [NEt4](2)[Re(CO)(3)Br-3] as a precursor and fully characterized by elemental analysis and spectroscopic methods. The analogous technetium-99m complexes were also prepared quantitatively using the [Tc-99m(CO)(3)(H2O)(3)](+) precursor and their structure corroborated by means of the rhenium complexes. The lipophilicity of the Tc complexes is in the range normally accepted for substances to be able to cross the BBB. Competition binding tests showed moderate affinity for the 5-HT1A receptors, with IC50 values at the nanomolar range (30 and 116 nM). Biodistribution in healthy animals was characterized by high initial blood and liver uptake and fast blood and tissue depuration with excretion taking place mainly through the hepatobiliary system. None of the new complexes showed any significant brain uptake, suggesting that the ability of a compound to cross the BBB is determined by more factors than charge, lipophilicity and size.