Stichelberger Albert, Waibel Robert, Dumas Cécile, Schubiger P A, Schibli Roger
Center for Radiopharmaceutical Science of the ETH Zürich, Paul Scherrer Institute Villigen and the University Hospital Zürich, CH-5232 Villigen, Switzerland.
Nucl Med Biol. 2003 Jul;30(5):465-70. doi: 10.1016/s0969-8051(03)00032-5.
A general synthetic approach for potent tridentate, bifunctional chelating agent (BFCA) for the M(CO)(3) fragment (M = (99g)Tc, (99m)Tc, and Re) has been elaborated. The strategy allows the facile preparation of BFCA with a pendent amino or carboxylic acid functionality for coupling to peptides and proteins via formation of an amide bond. [(5-amino-pentyl)-pyridin-2-yl-methyl-amino]-acetic acid (APPA) and [pyridin-2-yl-methyl-amino]-diacetic acid (PADA) were synthesized according to this protocol. The BFCA were labeled with the M(CO)(3) fragment, which resulted in formation of uniform products with a ligand to metal ratio of 1:1. The complexes have been fully characterized by means of mass spectrometry, IR, and NMR ((1)H, (13)C, (99)Tc) spectroscopy. Coordination of the tricarbonyl core with APPA and PADA was exclusively tridentate (via the acid function, the ternary amine, and the pyridine nitrogen). On the n.c.a. level the complexes were almost quantitatively formed (yield >90%) at ligand concentrations of 10+/-2 microM (PADA) or 50+/-4 microM (APPA) after 30 min at 70 degrees C. Chromatographic behavior of the (99m)Tc complexes is similar to that of the corresponding (99)Tc/Re complexes suggesting the identical chemical structure. Pharmacokinetic experiments with the (99m)Tc-APPA complex were performed in BALB/c mice and compared with previously published results of the (99m)Tc-PADA complex. The (99m)Tc-APPA complex revealed good clearance from the blood pool (0.29 +/- 0.03% ID after 24h p.i.) and a low uptake in the liver (2.41 +/- 0.14% ID/g), in the kidneys (2.81 +/- 0.12% ID/g) and other tissue and organs.
已精心设计出一种通用的合成方法，用于制备用于[M(CO)(3)]⁺片段（M = (99g)Tc、(99m)Tc和Re）的高效三齿双功能螯合剂（BFCA）。该策略能够轻松制备带有悬垂氨基或羧酸官能团的BFCA，以便通过形成酰胺键与肽和蛋白质偶联。[(5-氨基戊基)-吡啶-2-基甲基氨基]-乙酸（APPA）和[吡啶-2-基甲基氨基]-二乙酸（PADA）是根据此方案合成的。BFCA用[M(CO)(3)]⁺片段进行标记，从而形成配体与金属比例为1:1的均匀产物。这些配合物已通过质谱、红外光谱和核磁共振（¹H、¹³C、⁹⁹Tc）光谱进行了全面表征。三羰基核心与APPA和PADA的配位均为三齿配位（通过酸官能团、叔胺和吡啶氮）。在无载体添加水平下，在70℃下30分钟后，当配体浓度为10±2微摩尔（PADA）或50±4微摩尔（APPA）时，配合物几乎定量形成（产率>90%）。(99m)Tc配合物的色谱行为与相应的(99)Tc/Re配合物相似，表明化学结构相同。用(99m)Tc-APPA配合物在BALB/c小鼠中进行了药代动力学实验，并与先前发表的(99m)Tc-PADA配合物的结果进行了比较。(99m)Tc-APPA配合物显示出从血池的良好清除率（注射后24小时为0.29±0.03%注射剂量），在肝脏（2.41±0.14%注射剂量/克）、肾脏（2.81±0.12%注射剂量/克）以及其他组织和器官中的摄取量较低。
