Development of a rhenium-186-labeled MAG3-conjugated bisphosphonate for the palliation of metastatic bone pain based on the concept of bifunctional radiopharmaceuticals
Development of a rhenium-186-labeled MAG3-conjugated bisphosphonate for the palliation of metastatic bone pain based on the concept of bifunctional radiopharmaceuticals
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DOI：
10.1021/bc040249w
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发表时间：
2005-07-01
影响因子：
4.7
通讯作者：
Saji, H
中科院分区：
文献类型：
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作者：
Ogawa, K;Mukai, T;Saji, H
铼-186-1-羟基亚乙基-1，1-二膦酸盐（Re-186-HEDP）已用于缓解转移性骨痛。由于186 Re-HEDP在体内的不稳定性，在注射后观察到血液清除延迟和胃放射性摄取高。本研究基于双功能放射性药物的概念，设计了一种稳定的Re-186-巯基乙酰基甘氨酰甘氨酰甘氨酸（MAG_3）配合物-双膦酸盐[（4-羟基-4，4-二膦酰基丁基）氨甲酰基甲基]氨甲酰基甲基]氨甲酰基甲硫氨酸]氧合铼（V）（Re-186-MAG_3-HBP）。作为前体，通过N-[（三苯甲基巯基）乙酰基]甘氨酰甘氨酰甘氨酸（Tr-MAG 3）与双膦酸盐类似物的缀合来合成[1-羟基-1-膦酰基-4-[2-[2-[2-（2-三苯甲基巯基乙酰氨基）乙酰氨基]乙酰氨基]丁基]膦酸（Tr-MAG 3-HBP）。在Tr-MAG 3-HBP的三苯甲基脱保护后，通过在柠檬酸盐缓冲液中使（ReO 4-）-Re-186与SnCl 2反应来进行Re-186-标记。经HPLC纯化后，Re-186-MAG 3-HBP的放化纯度大于95%。为了比较Re-186-MAG 3-HBP和Re-186-HEDP的稳定性，将这些Re-186复合物在磷酸盐缓冲液中孵育。Re-186-MAG 3-HBP在24小时内未发生可测量的分解，而孵育后24小时仅约30%的Re-186-HEDP保持完整。在生物分布实验中，Re-186-MAG 3-HBP在骨中的放射性水平显著高于Re-186-HEDP。Re-186-MAG 3-HBP的血药清除率高于Re-186-HEDP。此外，Re-186-MAG 3-HBP放射性的胃蓄积低于Re-186-HEDP。总之，Re-186-MAG 3-HBP有望成为缓解转移性骨痛的有效放射性药物。
Rhenium-186-1-hydroxyethylidene-1,1-diphosphonate (Re-186-HEDP) has been used for the palliation of metastatic bone pain. Delayed blood clearance and high gastric uptake of radioactivity have been observed upon injection, due to the instability of 186Re-HEDP in vivo. In this study, on the basis of the concept of bifunctional radiopharmaceuticals, we designed a stable Re-186-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethio- late] oxorhenium(V) (Re-186-MAG3-HBP). As a precursor, [1-hydroxy-1-phosphono-4-[2-[2-[2-(2-tritylmercaptoacetylamino)acetylamino]acetylamino]acetylamino]butyl]phosphonic acid (Tr-MAG3-HBP) was synthesized by the conjugation of N-[(tritylmercapto)acetyl]glycylglycylglycine (Tr-MAG3) with the bisphosphonate analogue. After deprotection of the trityl group of Tr-MAG3-HBP, Re-186-labeling was performed by reacting (ReO4-)-Re-186 with SnCl2 in citrate buffer. After purification by HPLC, Re-186-MAG3-HBP showed a radiochemical purity of over 95%. To compare the stability of Re-186-MAG3-HBP and Re-186-HEDP, these Re-186 complexes were incubated in phosphate buffer. No measurable decomposition of Re-186-MAG3-HBP occurred over a 24-h period, while only approximately 30% of Re-186-HEDP remained intact 24 h postincubation. In biodistribution experiments, the radioactivity level of Re-186-MAG3-HBP in bone was significantly higher than that of Re-186-HEDP. Blood clearance of Re-186-MAG3-HBP was faster than that of Re-186-HEDP. In addition, the gastric accumulation of Re-186-MAG3-HBP radioactivity was lower than that of Re-186-HEDP. In conclusion, Re-186-MAG3-HBP is expected to be a useful radiopharmaceutical for the palliation of metastatic bone pain.