Rhemium-186-monoaminemonoamidedithiol-conjugated bisphosphonate derivatives for bone pain palliation
Rhemium-186-monoaminemonoamidedithiol-conjugated bisphosphonate derivatives for bone pain palliation
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DOI：
10.1016/j.nucmedbio.2006.03.006
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发表时间：
2006-05-01
影响因子：
3.1
通讯作者：
Saji, Hideo
中科院分区：
文献类型：
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作者：
Ogawa, Kazuma;Mukai, Takahiro;Saji, Hideo
为了开发一种用于缓解骨转移疼痛的放射性药物，基于双功能放射性药物的概念，我们合成了一种标记有Re-186(Re-186)的双膦酸衍生物，该衍生物在其双膦酸盐结构的中心碳上含有羟基，我们将稳定的Re-186-MAMA螯合物固定在4-氨基-丁叉-膦酸衍生物[N-[2-[[4-[(4-hydroxy-4，4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate]oxorhenum(V)的氨基上(Re-186-MAMA-HBP)，并通过与[N-[2-[3-(3，3-)-HBP])的比较研究了其双膦结构中心碳中心的羟基对羟基磷灰石亲和力和生物分布的影响Diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate]oxorhenium(V)(Re-186-MAMA-BP)。将Tr-MAMA衍生物偶联到4-amino-1-hydroxybutylidene-1，1-bisphosphonate.上，得到了Re-186-MAMA-HBP的前驱体三苯基(Tr)-MAMA-HBPTr-MAMA-HBP的Tr基团脱保护后，在柠檬酸缓冲液中与(ReO4-)-Re-186和SnCl2反应得到Re-186-MAMA-HBP。Re-186-MAMA-HBP经反相高效液相色谱分离后，放化纯度达95%以上。与Re-186-MAMA-BP相比，Re-186-MAMA-HBP在体外对羟基磷灰石微珠具有更强的亲和力，在体内的股骨蓄积水平显著高于Re-186-MAMA-BP。因此，在Re-186络合物共轭双膦酸盐中引入羟基将有效地促进骨骼中的蓄积。这些发现为寻骨治疗性放射性药物的设计提供了有用的信息。(C)2006 Elsevier Inc.保留所有权利。
To develop a radiopharmaceutical for the palliation of painful bone metastases based on the concept of bifunctional radiopharmaceuticals, we synthesized a bisphosphonate derivative labeled with rhenium-186 (Re-186) that contains a hydroxyl group at the central carbon of its bisphosphonate structure, we attached a stable Re-186-MAMA chelate to the amino group of a 4-amino-butylidene-phosphonate derivative [N-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (Re-186-MAMA-HBP) and we investigated the effect of a hydroxyl group at the central carbon of its bisphosphonate structure on affinity for hydroxyapatite and on biodistribution by conducting a comparative study with [N-[2-[[3-(3,3-diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (Re-186-MAMA-BP). The precursor of Re-186-MAMA-HBP, trityl (Tr)-MAMA-HBP, was obtained by coupling a Tr-MAMA derivative to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. Re-186-MAMA-HBP was prepared by a reaction with (ReO4-)-Re-186 and SnCl2 in citrate buffer after the deprotection of the Tr groups of Tr-MAMA-HBP. After reversed-phase high-performance liquid chromatography, Re-186-MAMA-HBP had a radiochemical purity of over 95%. Compared with Re-186-MAMA-BP, Re-186-MAMA-HBP showed a greater affinity for hydroxyapatite beads in vitro and accumulated a significantly higher level in the femur in vivo. Thus, the introduction of a hydroxyl group into Re-186 complex-conjugated bisphosphonates would be effective in enhancing accumulation in bones. These findings provide useful information oil the design of bone-seeking therapeutic radiopharmaceuticals. (c) 2006 Elsevier Inc. All rights reserved.