99mTc、153Sm和186,188Re-HEDTMP的合成及性质研究

【作者】 蒋树斌；

【导师】 罗顺忠；

【作者基本信息】 中国工程物理研究院 ， 核燃料循环与材料， 2001， 硕士

【摘要】 经Mannich胺甲基化反应，首次合成了新型配体HEDTMP（羟乙基乙二胺三甲撑膦酸）。在详细研究合成条件基础上，对其结构进行了表征。结果表明，在催化剂HCI与羟乙基乙二胺摩尔比大于3，甲醛（和亚磷酸）与羟乙基乙二胺摩尔比大于6时，80℃反应2h可获得收率大于77％（以胺计）的HEDTMP；经IR、¹H—NMR和元素分析确认合成是成功的。测定了HEDTMP酸离解常数。显示化合物在中性pH下能有效生成含孤对电子的氧负离子，提示化合物与金属离子可望生成稳定配合物。 首次选择具有优良核性质的几种核素^99mTC、^186,188Re、¹⁵³Sm，详细研究了上述核素与配体HEMTMP配位的影响因素、配合物配位形成条件及稳定性；测定配合物的脂水分配系数；分析了实验条件下Re-HEDTMP中心离子氧化态及Sm-HEDTMP的化学计量组成。研究表明，对于Tc-HEDTMP，介质pHO.5-0.8，还原剂量大于0.25mg，配体量大于3.0mg时可生成配合产率（以Tc计）大于96％的配合物；介质pH为酸性和中性有利于配合物稳定，配体量增加有利于配合物稳定，配合物的稀释对其稳定性有一定影响，但实验条件下稀释100倍48h时配合产率仍高于95％。对Sm-HEDTMP，介质为中性到弱碱性有利于配合物形成，配体量增加有利于提高Sm配合产率；稳定性研究表明，Sm配合物在弱碱性和中性介质中有很高的稳定性，虽然酸性介质对其稳定性有一定影响，但配合物在pH4.0时放置7d配合产率仍不低于96％（以Sm计）；同Tc-HEDTMP相似，配体量增加会提高配合物稳定性。对Re-HEDTMP，酸性介质有利于配合物形成，配体增加对配合产率的提高有利，还原剂量不能太大，否则要求更多的配体以防止出现白色沉淀；配体量增加、保护剂加入、载体Re加入、还原剂量适当提高都会有助于配合物的稳定；碱性介质、高倍稀释都会影响配合物的稳定。研究还表明，Sm-HEDTMP的组成为Sm:HEDTMP=1:1，Re-配合物中心离子Re的氧化态主要为+5价；脂水分配系数分别为Tc、Sm和Re-HEDTMP2.1×10^-4，4.0×10^-4，3.9×10^-4。 首次评价了配合物的生物体内行为，结果表明；兔骨显像良好，其四肢、脊椎和颅骨图橡清晰可见；小鼠体内分布表明配合物主要浓集在小鼠骨骼系统，24h时Sm、Tc、Re配合物的骨摄取分别为18.90％、11.8％和7.7ID％/（克组织），配合物血清除快，软组织如肌肉、肝脏及肾脏的摄取率很低。与常用的药物^99mTC-MDP、^186,188Re-HEDP、¹⁵³Sm-EDTMP相比，^99mTC-HEDTMP兔显像清晰；¹⁵³Sm-HEDTMP及^186,188Re-HEDTMP骨摄取高于¹⁵³Sm-EDTMP和^186,188RE-HEDP，显示合成的配合物是很有希望的骨肿瘤药物。 采用计算机模拟，分析了Sm、Re-HEDTMP配位过程的能量及配体配位原子电荷变化，给出了最可能配位原子及其配位顺序。更多还原

【Abstract】 HEDTMP [N- (2- hydroxyethyl) ethlenediamine- 1,1 ,2-tri(methylene phosphonic acid)] is firstly synthesized undergoing Mannich reaction. The condition of synthesis is investigated, and HEDTMP is characterized in detail. Results show that the yield of HEDTMP is more than 77% when the mole ratio of catalyst HC1 to HEDA [N- (2- hydroxyethyl) ethlenediamine] is more than 3 and methanal (phosphorous acid) to HEDA is more than 6 after the process of reaction at 80? 0C for 2h. The IR, 慔- NMR and elemental analysis are carried out to identify HEDTMP, and make certain synthesis is successful. The determined absorption constant show HEDTMP can produce & which can provide isolated pair of electron to coordinate with metallic ion. So HEDTMP is a potential ligand to form complexes with Re, Tc or Sm. The formation conditions, stability and distribution coefficient K~ between oil and water of complexes are investigated, and molecular component of Sm-HEDTMP and oxidation state of Re in Re-HEDTMP are determined. As for Tc compound, the yield is more than 96%, when HEDTMP is more than 3mg and.reducing agent SnC12 is more than 0.25 mg, pHO.5-8. Acidic and mediate pH is favorable to the stability of Tc-HEDTMP. The compound is more stable increasing ligand. It is unfavorable when the complex is diluted, but the coordination yield of Tc is still more than 95% when the factor of dilution is 100 after 48h. As for Re complex, acidic media is favorable to complex and the coordination yield of Re is higher increasing ligand, but it is easy to form white precipitation when increase the concentration of SnC12 though the coordination field of Re could be higher increasing reducing agent. The increasing of ligand and reducing agent, the adding of anti-oxidation agent and carrier promote the stability of Re-HEDTMP, but basic media is not favorable to the stability of Re- HEDTMP. As for Sm complex, it is favorable to complex in mediate to weakly basic media, and the coordination field of Sm is higher when ligand is increased. The compound is stable in mediate and acidic media, and increasing ligand increase the stability. The Sm compound is so stable that the coordination field is more than 96% after 7d in media pH4, and the dilution do not effected field. The results also show that, the mole ratio in Sm-HEDTMP is Sm:HEDTMP = 1:1, the Re oxidation state in Re-HEDTMP is +5, the K0~ is Tc-HEDTMP2. lxi 0~, Sm-HEDTMP4.Ox 1 0~? Re- HEDTMP3 .9x 1 0~ respectively. Animal experiment is conducted on rabbits and mice. SPECT scanning on rabbits show Tc, Re and Sm-LIEDTMP are mainly absorbed by skeleton. The images are clear and legs, spine and skull can be observed clearly. Mice trial show injected compounds are concentrated mainly on skeletal system, the uptake of skeleton of Tc, Re and Sm complex are 7.7, 18.9, 11.8 ID % /g organ respectively at 24h, and the clearance of blood are quick, the retaining on un-targeting organ are very small. In a word, 3 complexes are promising potential radiopharmaceuticals for bone tumor. The coordination process of Sm-HEDTMP and Re-HEDTMP are analyzed by theoretical computation. The most possible atom to coordinate and the order of coordination are given.更多还原