Fernandes C, Correia J D G, Gano L, Santos I, Seifert S, Syhre R, Bergmann R, Spies H
Departamento de Química, ITN, Estrada Nacional 10, 2686-953 Sacavém Codex, Portugal.
Bioconjug Chem. 2005 May-Jun;16(3):660-8. doi: 10.1021/bc049718k.
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.
通式为[(⁹⁹ᵐ)Tc(O)(κ³ - PNX)(κ¹ - SPh)] [X = O (1a), S (2a)]的混合配体模型配合物是使用氯化亚锡作为还原剂，由[(⁹⁹ᵐ)TcO₄⁻]通过一步法制备而成。稳定性研究以及与谷胱甘肽的挑战实验表明，配合物2a展现出了开展动物研究的良好特性。在注射后5分钟（0.14% ± 0.03）和120分钟（0.11% ± 0.02）时，脑部的活性（注射剂量/器官的百分比）促使人们合成了几种通式为[M(O)(κ³ - PNS)(κ¹ - SL)]（M = (⁹⁹ᵐ)Tc，3a - 6a，Re，3 - 6）的混合配体“3 + 1”氧代配合物，其中三齿配体是杂功能化膦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（HSL1 - HSL4）。通过比较(⁹⁹ᵐ)Tc配合物在HPLC色谱图中的保留时间（γ检测）与类似Re配合物在254 nm处的保留时间（UV检测），对(⁹⁹ᵐ)Tc配合物进行了表征。经HPLC纯化后，放射化学纯度高于95%的(⁹⁹ᵐ)Tc配合物在生理盐水、0.01 M PBS（pH 7.4）、大鼠血浆（4小时，37℃）和谷胱甘肽（10 mM溶液，2小时，37℃）中均稳定。测定了对5 - HT₁A受体的结合亲和力和选择性（相对于5 - HT₂A受体），配合物5表现出最佳值（5 - HT₁A的IC₅₀为2.35 ± 0.02 nM；竞争剂5 - HT₂A为372 ± 11 nM）。在小鼠体内进行的生物分布和稳定性研究表明，其排泄途径以肝胆为主，体内稳定性高，但脑摄取较差。
