Institute of Radiopharmacy, Forschungszentrum Dresden Rossendorf, PO Box 510 119, 01314 Dresden, Germany.
Nucl Med Biol. 2011 Apr;38(3):399-415. doi: 10.1016/j.nucmedbio.2010.09.006. Epub 2010 Dec 3.
We report on an efficient procedure for the preparation of [(188)Re(N)(PNP)]-based complexes (where PNP is diphosphinoamine) useful in the development of target-specific radiopharmaceuticals. The radiochemical yield of the compounds was optimized considering such reaction parameters as nature of the nitrido nitrogen donor, reaction times and pH level. The chemical identity of the (188)Re agents was determined by high-performance liquid chromatography comparison with the corresponding well-characterized cold Re compounds. (188)Re(N) mixed compounds have been evaluated with regard to stability toward transchelation with GSH and degradation by serum enzymes. The clearance of selected radiocompounds from normal tissues and their in vivo stability were evaluated in rats by biodistribution and imaging studies. (188)Re(N)(cys ∼)(PNP) mixed-ligand compounds were efficiently prepared in aqueous solution from perrhenate using a multistep procedure based on the preliminary formation of the labile (188)Re(III)-EDTA species, which easily undergo oxidation/ligand exchange reaction to afford the (188)Re(V) ≡ N core in the presence of dithiocarbazate. The final mixed-ligand compounds were obtained, at 100 °C, by adding the two bidentate ligands to the buffered (188)Re(V) ≡ N solution (pH 3.2-3.6). However, a relatively high amount of cys ∼ ligand was required to obtain a quantitative radiochemical yield. The complexes were stable toward reoxidation to perrhenate and ligand exchange reactions. In vivo studies showed rapid distribution and elimination of the complexes from the body. No specific uptakes in sensitive tissues/organs were detected. A positive correlation of the distribution of the complexes estimated with biodistribution studies (%ID) and with micro-SPECT semiquantification imaging analysis (standard uptake values) was observed. These results support the possibility of applying [(188)Re(N)(PNP)] technology to the preparation of target-specific agents.
我们报告了一种有效的制备基于 [(188)Re(N)(PNP)] 的配合物的方法，这些配合物在开发靶向放射性药物方面非常有用。我们考虑了反应参数（如氮供体的性质、反应时间和 pH 值）来优化化合物的放射化学产率。通过与相应的特征明确的冷 Re 化合物进行高效液相色谱比较，确定了 (188)Re 试剂的化学性质。评估了 (188)Re(N) 混合化合物对 GSH 转金属和血清酶降解的稳定性。通过生物分布和成像研究在大鼠中评估了选定放射性化合物从正常组织中的清除率及其体内稳定性。(188)Re(N)(cys ∼)(PNP) 混合配体化合物可以通过基于初步形成不稳定的 (188)Re(III)-EDTA 物种的多步程序，从高铼酸盐在水溶液中有效制备，该物种容易发生氧化/配体交换反应，在半胱氨酸存在下提供 (188)Re(V)≡N 核。通过将两种双齿配体添加到缓冲的 (188)Re(V)≡N 溶液（pH 3.2-3.6）中，在 100°C 下获得最终的混合配体化合物。然而，需要相对大量的 cys ∼ 配体才能获得定量的放射化学产率。该配合物对重新氧化为高铼酸盐和配体交换反应稳定。体内研究表明，复合物从体内快速分布和消除。在敏感组织/器官中未检测到特定摄取。用生物分布研究（%ID）和微 SPECT 半定量成像分析（标准摄取值）估计的复合物分布之间观察到正相关。这些结果支持将 [(188)Re(N)(PNP)] 技术应用于制备靶向特异性试剂的可能性。
