新型骨显像剂99Tcm-BIPrDP的制备及其反应动力学研究

Preparation and Reaction Kinetics of a New Bone Imaging Agent 99Tcm-BIPrDP

  • 摘要: 以2-丁基咪唑为原料,经过N-烷基化、酯水解和磷酰化三步反应,合成了一种新型双膦酸配体1羟基-3-(2-丁基-1H -咪唑-1-基)丙烷-1,1-双膦酸(BIPrDP),目标产物和中间体经过元素分析、质谱、核磁共振氢谱进行了结构鉴定。在SnCl2还原下,用Na99TcmO4对BIPrDP进行标记,得到一种新型骨显像剂99Tcm-BIPrDP,进而对99Tcm-BIPrDP进行反应动力学研究。在40、50、60、70、80和90 ℃时的反应速率常数k分别为0.018 3、0.020 7、0.024 1、0.027 0、0.028 8和0.031 9。温度与反应速率常数k的关系为lnk=-1 267.1×1/T+0.055(r2=0.990 2),反应活化能Ea=10.53kJ·mol-1,远低于一般化学反应活化能 (典型值20~150 kJ·mol-1),表明99Tcm-BIPrDP的制备反应较容易进行。同时,通过测定不同温度下的标记率RLY可得RLY与温度的关系:lnRLY/(1-RLY)=-6 218.4/T+19.84。为使标记率大于90%,反应温度必须高于79.31 ℃。

     

    Abstract: A new diphosphonic acid ligand, 1-hydroxy 3-(2-butyl-1H-imidazol-1-yl)propane-1,1-diyldiphosphonic acid (BIPrDP), was prepared from the starting material 2-butyl-1H-imidazole by three steps of reactions: N-alkylation, ester hydrolysis and phosphoric acid acylation. The structures of the intermediate and target compounds were identified by elemental analysis, MS and 1H-NMR. BIPrDP was directly labeled by Na99TcmO4 in the presence of the reducing agent SnCl2 to afford a new bone imaging agent 99Tcm-BIPrDP. The kinetics of the labeling reaction between BIBrDP and 99TcmO4- was also studied. The reaction rate constants, k, were determined to be 0.018 3, 0.020 7, 0.024 1, 0.027 0, 0.028 8, 0.031 9 at 40、50、60、70、80 and 90 ℃, respectively. The correlation between the reaction rate constant k and temperature T was ln k =-1 267.1×(1/T)+0.055(r2=0.990 2). The reaction activation energy, Ea, was found to be 10.53 kJ·mol-1, much lower than the activation energy of general chemical reactions (typically 20~150 kJ·mol-1), which was consistent with the observation that the preparation of 99Tcm-BIPrDP took place rapidly. In addition, based on the data of the radiolabeling yield (RLY) at different temperatures, a correlation between the RLY and temperature was developed as lnRLY/(1-RLY)=-6 218.4/T+19.84. This correlation suggests that, in order to achieve radiolabeling yields of higher than 90%, the reaction temperature should be higher than 79.31 ℃.

     

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