~(99)Tc~m(CO)_3(H_2O)_3~+标记的新双功能联接剂的研究
Research of Novel Bifunctional Chelating Agents for the Tc-tricarbonyls Precursor[~(99)Tc~m(CO)_3(H_2O)_3]~+
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摘要: 设计合成了3种新的小分子三齿配体NNS 1,NNS 2,NSN,并设计合成了文献报道的NNO三齿配体。它们作为双功能联接剂可以连接受体、多肽、蛋白等靶向性分子,用于设计合成新的以99Tcm(CO)3为核心的放射性药物。标记条件实验证明,3种新配体在配体量极低(10μg)、在较短的反应时间内(10min),配体标记率可以达到95%以上,放射化学纯度大于90%,均为高效的双功能联接剂;电泳实验和脂溶性实验表明:NNS 1,NNS 2,NSN与羰基锝标记后,锝配合物显示不同价态;稳定性实验证明,3种标记均具有很高的体外稳定性,标记后6h内基本不分解;GSH,L 半胱氨酸体外竞争稳定性实验证明其不易受到裸露-SH的进攻,因而在体内也会有较高的稳定性;小鼠动物分布试验表明,3个配合物均能较快地从血液和多数组织器官中清除,主要在肝脏浓集,是较理想的标记99Tcm(CO)3(H2O)3+的双功能联接剂。Abstract: The organometallic precursor fac-[~(99)Tc~m(OH_2)_3(CO)_3]~+ is reacted with three novel tridentate ligands (NNS-1,NNS-2,NSN) and the propertices of their ~(99)Tc~(m) compleses in vivo and in vitro have been evaluated.One tridentate ligand (NNO),which has been reported by Alberto R.ect.,is also synthesized. The results of labeling condition experiments indicate that a radiochemical purity higher than 90% can be obtained within a very short time (10 min) by the reaction of fac-[~(99)Tc~m(CO)_3]~+ core in a slightly acidic condition (pH=4.0~6.0) with a very small amount (10 μg) of these three new ligands. Two of the complexes (NNS-1,NNS-2) are electrically neutral and lipophilic evidenced by electrophoretic investigations.And another comples (NSN) is cationic and hydrophilic.It showe that the three ligands can be used as alternative bifumctional chelating ligands at different conditions. Stablility experiments and competition experiments with glutathion (GSH) and L -cysteine respectively show that the three novel tridentate complexes have a high stability in vitro . Biodistribution studies in mice demonstrate all three complexes are fast cleared from the blood and organs other than liver.Two of the complexes (NNS-1,NNS-2)have some uptake in heart,and fast clearance and have low uptake in brain.