Mastrostamatis S G, Papadopoulos M S, Pirmettis I C, Paschali E, Varvarigou A D, Stassinopoulou C I, Raptopoulou C P, Terzis A, Chiotellis E
Institute of Radioisotopes-Radiodiagnostic Products, NCSR Demokritos, Aghia Paraskevi, Athens, Greece.
J Med Chem. 1994 Sep 30;37(20):3212-8. doi: 10.1021/jm00046a004.
In developing 99mTc complexes as potential brain-imaging agents, we investigated the coordination chemistry of ligands containing sulfur and nitrogen donor atoms with the general formula R-CH2CH2N(CH2CH2SH)2 (R = C2H5S, (C2H5)2N). These ligands act as tridentate SNS chelates to the TcO3+ core, leaving open one coordination site cis to the oxo group. In reactions with the highly reactive [99TcOCl4]- precursor, this vacancy was occupied by a chlorine atom. When the ligands reacted in the presence of 4-methoxythiophenol, using 99Tc(V)-gluconate as precursor, the vacancy was filled with 4-methoxythiophenol, which acted as coligand. Thus neutral mixed ligand complexes of the general formula [TcO((SCH2CH2)2NCH2CH2R)X], where X = Cl or 4-methoxythiophenol, were synthesized. The complexes were characterized by UV-vis, IR, 1H NMR, crystallographic, and elemental analyses. The crystal structures of 3a (R = C2H5S, X = Cl) and 4b (R = (C2H5)2N, X = 4-methoxythiophenol) demonstrated that the coordination geometry is trigonal bipyramidal with the N1 and Cl or S3 occupying the apical positions and the basal plane defined by the S1 and S2 of the tridentate ligand and the oxo group. The complexes 4a(99mTc) (R = C2H5S, X = 4-methoxythiophenol) and 4b(99mTc) were prepared using 99mTc-glucoheptonate as precursor and were purified by HPLC. Biodistribution in mice showed high initial brain uptake (3.68% and 3.56% dose/organ for 4a(99mTc) and 4b(99m-Tc), respectively). Complex 4b(99mTc) displayed significantly higher brain/blood values and prolonged retention in brain as well. The results suggest that structural modifications based on configurations 4a,b may provide novel 99mTc brain-imaging agents with improved biological characteristics.
在研发作为潜在脑显像剂的99mTc配合物时，我们研究了通式为R-CH2CH2N(CH2CH2SH)2（R = C2H5S，(C2H5)2N）的含硫和氮供体原子的配体的配位化学。这些配体作为TcO3+核心的三齿SNS螯合剂，在氧代基团的顺式位置留下一个空的配位位点。在与高活性的[99TcOCl4]-前体反应时，这个空位被一个氯原子占据。当配体在4-甲氧基苯硫酚存在下反应，使用99Tc(V)-葡萄糖酸盐作为前体时，空位被4-甲氧基苯硫酚填充，4-甲氧基苯硫酚作为共配体。因此，合成了通式为[TcO((SCH2CH2)2NCH2CH2R)X]的中性混合配体配合物，其中X = Cl或4-甲氧基苯硫酚。通过紫外可见光谱、红外光谱、1H核磁共振、晶体学和元素分析对配合物进行了表征。3a（R = C2H5S，X = Cl）和4b（R = (C2H)2N，X = 4-甲氧基苯硫酚）的晶体结构表明，配位几何形状为三角双锥，N1和Cl或S3占据顶端位置，由三齿配体的S1和S2以及氧代基团定义基面。配合物4a(99mTc)（R = C2H5S，X = 4-甲氧基苯硫酚）和4b(99mTc)使用99mTc-葡庚糖酸盐作为前体进行制备，并通过高效液相色谱法进行纯化。在小鼠体内的生物分布显示出较高的初始脑摄取量（4a(99mTc)和4b(99mTc)分别为3.68%和3.56%剂量/器官）。配合物4b(99mTc)还显示出显著更高的脑/血比值以及在脑中的滞留时间延长。结果表明，基于4a、b构型的结构修饰可能会提供具有改善生物学特性的新型99mTc脑显像剂。
