Dramatic effect of the tridentate ligand on the stability of 99mTC "3 + 1" oxo complexes bearing arylpiperazine derivatives.
Dramatic effect of the tridentate ligand on the stability of 99mTC "3 + 1" oxo complexes bearing arylpiperazine derivatives.
复制标题
三齿配体对带有芳基哌嗪衍生物的 99mTC“3 1”氧配合物的稳定性具有显着影响。
DOI：
10.1021/bc049718k
复制
发表时间：
2005
影响因子：
4.7
通讯作者：
H. Spies
中科院分区：
文献类型：
--
作者：
C. Fernandes;J. Correia;L. Gano;I. Santos;S. Seifert;R. Syhre;R. Bergmann;H. Spies
以[（99 m）Tc O（4）（-）]为原料，氯化亚锡为还原剂，一步合成了通式为[（99 m）Tc（O）（kappa（3）-PNX）（kappa（1）-SPh）] [X = O（1a），S（2a）]的混合配体模型配合物。谷胱甘肽的稳定性研究和挑战实验表明，复合物2a提出了有前途的功能，追求动物研究。大脑中的活动5 min时（注射剂量%/器官）（0.14% +/- 0.03）和120 min（0.11% +/-0.02）pi促进了通式[M（O）（kappa（3）-PNS）（kappa（1）-SL）]的几种混合配体“3 + 1”氧代配合物的合成（M =（99 m）Tc，3a-6a，Re，3-6），其中三齿配体是杂官能化膦2-（二苯基膦基）-N-（2-硫代乙基）苯甲酰胺（PNS），共配体是不同的芳基哌嗪衍生物（HSL 1-HSL 4）。通过比较它们在HPLC色谱图中的保留时间（γ-检测）与类似Re络合物的保留时间（在254 nm处的UV检测），表征了（99 m）Tc络合物。在HPLC纯化后，以高于95%的放射化学纯度获得的（99 m）Tc络合物在盐水、0.01 M PBS（pH 7.4）、大鼠血浆（4 h，37 ℃）和谷胱甘肽（10 mM溶液，2 h，37 ℃）中是稳定的。测定了对5-HT（1A）受体的结合亲和力和选择性（相对于5-HT（2A）受体），复合物5显示出最佳值（5-HT（1A）的IC（50）为2.35 +/- 0.02 nM;竞争对手5-HT（2A）为372 +/- 11 nM）。小鼠中的生物分布和稳定性研究表明，优先肝胆排泄，体内稳定性高，但脑摄取较差。
Mixed-ligand model complexes of general formula [(99m)Tc(O)(kappa(3)-PNX)(kappa(1)-SPh))] [X = O (1a), S (2a)] were prepared in a one-step procedure from [(99m)TcO(4)(-)] using stannous chloride as reducing agent. Stability studies and challenge experiments with glutathione showed that complex 2a presented promising features for pursuing animal studies. The activity in the brain (% dose injected/organ) at 5 min (0.14% +/- 0.03) and 120 min (0.11% +/- 0.02) pi encouraged the synthesis of several mixed-ligand "3 + 1" oxo complexes of general formula [M(O)(kappa(3)-PNS)(kappa(1)-SL))] (M = (99m)Tc, 3a-6a, Re, 3-6), in which the tridentate ligand is the heterofunctionalized phosphine 2-(diphenylphosphanyl)-N-(2-thioethyl)benzamide (PNS) and the co-ligands are different arylpiperazine derivatives (HSL1-HSL4). The (99m)Tc complexes have been characterized by comparison of their retention times in the HPLC chromatogram (gamma-detection) with the retention times of the analogous Re complexes (UV detection at 254 nm). The (99m)Tc complexes, obtained with radiochemical purity higher than 95%, after HPLC purification, are stable in saline, 0.01 M PBS (pH 7.4), rat plasma (4 h, 37 degrees C), and glutathione (10 mM solutions, 2h, 37 degrees C). Binding affinity and selectivity for 5-HT(1A) receptors (relative to the 5-HT(2A) receptor) were determined, complex 5 demonstrating the best values (IC(50) for the 5-HT(1A) 2.35 +/- 0.02 nM; competitor 5-HT(2A) 372 +/- 11 nM). Biodistribution and stability studies in mice indicated a preferred hepatobiliary excretion, a high in vivo stability, but a poor brain uptake.