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~(99m)TC、~(186,188)Re、~(153)Sm，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~(99m)TC-MDP、
~(186,188)Re-HEDP、~(153)Sm-EDTMP相比，~(99m)TC-HEDTMP兔显像清晰；~(153)Sm-HEDTMP
及~(186,188)Re-HEDTMP骨摄取高于~(153)Sm-EDTMP和~(186,188)RE-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。
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.
引文
1． Tofe AJ, Francis MD, Harvey WJ. Correlation of Neoplasms with Incidence and Location of Skeletal Metastases: An Analysis of Diphosphonate Bone Scans. J Nucl Med. 1975; 16:986．
2． Citrin DL, Bessent RG, Greig WR, et al. A Comparison of The Sensitivity and Accuracy of The 99m-Tc-Phosphonate Bone Scan and Skeletal Radiography in The Diagnosis of Metastases. Clin Radiol. 1977; 28: 107．
3． Citrin DL, Bessent RG, Mcginlay E, et al. Dynamic Studies with 99mTc HEDP in Normal Subjects and in Patients with Bone Tumors. J Nucl Med. 1975; 16:886．
4． Rohlin M. Nosslin B. Quantitative Analysis of The Distribution of 99m Tc-labeled Ethylene Hydroxy Diphosphonate in Young Rats. Eur J Nucl Med. 1977; 2:113．
5． Serafmi AN. Paget's Disease of Bone. Semin Nucl Med. 1976; 6:47．
6． Jones AG, Francis MD, Davis MA. Bone Scanning: Radionuclide Reaction Mechanism. Semin Nucl Med. 1976; 6:3．
7． Zimmer AM. Isitman AT. Holmes R. Enzymatic Inhibition of Diphosphonate: A Proposed Mechanism of Tissue Uptake. J Nucl Med. 1975; 16:352．
8． Rosenthall L. Kaye M. Technitium-99m-pyophosphate Kinetics and Imaging in Metabolic Bone Disease. J Nucl Med. 1975; 16:33．
9． Francis MD. The Inhibition of Calcium Hydroxyapatite Crystal Growth by Polyphosphonates and Polyphosphates. Calcif Tissue Res. 1969; 3:151．
10． Tilden RL, Jackson JJ, Enneking WF, et al. 99m Tc-polyphosphonate: Histological Localisation in Human Femurs By autoradiography. J Nucl Med. 1973; 14: 576．
11． 吕恭序，陆洁，唐志刚，等．一种新型骨显像剂99mTc-AEDP的初步研究．同位素，1997；10： 232．
12． Clanton JA. Radiopharmaceutics in Nuclear Medicine. In: Essentials of nuclear Medicine Science (Edited by HIadik WB, Saha GB and Study KT) Williams & Wilkins, Baltimore. 1987．
13． Hosain P and Wang TST. Bone imaging Compounds with Special Reference to Structure-Affinity Relationship. In: Radiopharmaceuticals Structure-Affinity Relationships (Edited by Spencer RP), pp. 531-537． Grune & Stratton, New York.
14． Consuelo AM, Laura MA, Carlos MM, et al. Radiopharmacokinetic Data for 99mTc-ABP-A New Radiopharmaceutical for Bone Scanning: Comparison with 99mTC-MDP. Nucl Med Biol. 1997; 24: 27．
15． Silberatein EB, Elgazzar AH, and Kapilivsky A. Phosphorus-32 Radiopharmaceuticals for The Treatment of Painful Osseous Metastases. Semin Nucl Med. 1992; 22: 17．
16． Robinson RG，Preston DF,Spicer JA，et al．Radionuclide Therapy of Intractable Bone Pain： Emphasis on Strontium-89． Sem/n Nucl Med．1992；22：28．
17． De Ligny CL，Geisema WJ，Hoevelaken TPM，et al．Investigation of Two New[99m~Tc]Tc-HEDP Preparations That Can Be Excepted to Give a Better Lesion-to-normal-bone Uptake Ratio When Used as Bone Scanning Agents．Nucl Med Biol．1993；20：23．
18． Fleisch H．Bisphosphonates in Osteoporosis：An Introduction．Osteoporosis Int．1993；3：3．
19． Watts NB．Treatment of Osteoporosis with Bisphosphonate．Rheum Dis Clin North Am．1994； 20：17．
20． Tse JW,Wiebe LI，and Noujaim AA．High Specific Activity[Samarium-153] EDTA for Imaging of Experiment Tumor Models．J Nucl Med．1989，30：202．
21． Atkins HL，Mausner LF,Srivastava SC，et al．Biodistribution of Sn-117m(4+)DTPA for Palliative Therapy of Painful Osseous Metastases．RadioL.1993；186：279．
22． Volkert WA，and Hoffman TJ．Therapheutic Radiopharmaceuticals．Chem Rev．1999，99：2262．
23． Turner JH，Martindale AA．Samarium-153 Chelate Localization in Maligant Melanoma．Eur J Nucl Med．1987；13：432．
24． 罗顺忠，蒲满飞，李玉谦，等．骨肿瘤治疗药物的研究 I．153~Sm及153~Sm-EDTMP的制备． 核化学与放射化学.1991;13：233．
25． 蒋树斌，谯健，罗顺忠，等．186~Re-PMT 的研制．第五届全国核化学与放射化学学术研讨 会．1997． 5，北京．
26． Luo Shunzhong，Pu Manfei，Qiao Jian，et al．Formation of a Potential Tumor Therapeutic Pharmaceutical 186~Re-bleomycin．Nucl Sci and Tech．1998；16：96．
27． 邓候富，罗顺忠，谭天秩，等．186Re-HEDP 的制备及动物实验．中华核医学杂志．1994; 14：158．
28． Mathieu L，Chevalier P,Galy G，et al．Preparation of Rhenium-186 Labelled EHDP and Its possible Use in the Treatment of Osseous Neoplasms．Int JAppl Radiat Isot．1979；30：725．
29． 谯健．铼放射性药物研究．第五届全国核化学与放射化学学术研讨会．1997． 5，北京．
30． 王豫庆，贾兵，金小海，等．188~Re-EDTMP 的制备及其小鼠体内分布．同位素．2000; 13：157．
31． 孙耀中，罗顺忠．188~Re-DTPMP 的合成及生物分布初探．孙耀中硕士论文．
32． Alyafei S，Tomiyoshi K，Sarwar M，et al．Biodistribution Studies of the 186~Re Complex of 3-amino-1-hydroxypropylidene-1，1-Bisphosphonic Acid in Mice．Nucl Med Commun．1999;20： 551．
33． Kazuyuki Hashimoto．Labelling of AminOmethyIenephOsphOnate Derivatives with Generator-produced188~Re，and a Study oftheir Stability．Appl Radiat Isot．1999；51：307．
34． Kothari K，Pillai MRA，Unni PR，et al．Preparation，Stability Studies and Pharmacological Behavior of[186~Re]Re-HEDP．Appl Radiat lsot．1999；51：51．
35． Seifert S，Hoepping A，Klostermann K，et al．Preparation and Characterization of Novel Mixed-ligand Oxorhenium(V)and Oxotechnetium(V)Complexes Bearing up to Four Ester Groups．Appl Radiat lsot．1997；48：943．
36． Hansen L，Xiaolong X，Kwok TY,et al．Solution Studies of Re~vO(anti-D-penicillamina to-N，S，O)(syn-D-penicillaminato-N，S)．Inorg Chem．1996；35：1958．
37． Reddy VS，Bernign DE，Katti KV,et al．Chemistry in Environmentally Benign Media． Synthesis and Characterization of Rhenium(V)Complexes Derived from Novel Water-Soluble (Hydroxymethyl)phosphines．Crystal Structures of[Re(O)_2{(HOH_2C)_2PC_6H_4P(CH_2 OH)_2 ]_2}_2] I and[Re(O)_2{(HOH_2C)_2PC_2H_4P(CH_20H)_2}2] Cl．Inorg Chem．1996；35：1753．
38． Lihsueh(Sherry) Chang，Sen-lchi Aizawa,Mary Jane Heeg，et al．Synthesis and Chara cterization of the(Thiolato)Rhenium(III)Complexes．Trans-[Re(SR)2(R’2PCH2CH2PR’2) 2] _+，Where R is an AIkyl，Benzyl，or Phenyl Group and R’is an Ethyl or Phenyl Gr oup．Single-Crystal Structure Analysis of Trans-[Re(SC_6H_5) _2(Et_2PCH_2CH_2PEt_2) _2] PF6，Tra ns-[Re(SC_6H_4-P-CH_3) _2(Et_2PCH_2CH-2PEt_2) _2] PF_6，and Trans-[Re(SC_6H_5) _2(Ph_2PCH_2CH_2PPh_2) 2] CF_3SO_3． 1/2NCCH_3． Inorg Chem．1991；30：4920．
39． Alyafei S，Tomiyoshi K，Sarwar M，et al．Biodistribution Studies of the 186_Re Complex of 3-amino-l-hydroxypropylidene-l．l-bisphosphonic Acid in Mice．Nucl Med Commu．1999；20： 551．
40． O’Mara RE，Mcafee JG，Subramanian G．Rare Earth Nuclide as Potential Agents for Skeletal Imaging．J Nucl Med．1969；10：49．
41． Goeckeler WF, Edwards B，Volkert WA，et al．Skeletal Localization of Samarium-153 Chelates：Potential Therapeutic Bone Agents．J Nucl Med．1987；28：495．
42． 罗顺忠，蒲满飞，谯健，等．骨肿瘤治疗药物的研究．．153_Sm-EDTMP 的生物性质评 价. 核化学与放射化学. 1994；16：96．
43． 邓候富，谭天序，匡安仁，等．新的骨显像及骨肿瘤治疗剂153_Sm-EDTMP 的初步应用． 中华核医学杂志.1992；12：27．
44． 罗顺忠，蒲满飞，谯健，等．153_Sm-氨羧配合物在羟基磷灰石晶体上的吸附研究．待发表 资料．
45． Subramanian G，Mcafee JG，Thomas FD，et al．New Diphosphonate Compounds for Skeletal Imaging：Comparison with Methylene Diphosphonate．Radiol．1983；149： 823．
46． Laznicek M，Laznickova A，Budsky F，et al．Comparison of Biological
Characteristics of EDTMP Complexes with 99m_Tc,111_In and 153_Sm in Rats．Appl Radiat Isot．1994；45：949．
47． 汤磊，魏洪源．64_Cu-胺基膦酸配合物的制备．中物院核物理与化学研究所内部资料．
48． Subramanian G，Mcafee JG，Blair RJ，et al．Technetium-99m-Methylene Diphosphonate--a Superior Agent for Skeletal Imaging：Comparison with Other Technetium Complexes．J Nucl Med,1975；16：744．
49． Ketring AR．153_Sm-EDTMP and 186_Re-HEDP as Bone Therapeutic Radiopharmaceuticals． Nucl Med Biol．1987；14：223．
50． Marion D，Francis and Rosemary L．The Development of Diphosphonates as Significant health Care Products．J Chem Edu．1978；55：761．
51． Kazuyuki Hashimoto．Synthesis of a 188_Re-HEDP Complex Using Carrier-free 188_Re，and a Study of Its Stability．Appl Radiat isot．1998；49：351．
52． 罗顺忠，谯键，蒲满飞，等．Sm，In，Re和Tc-EDTMP 配合物性质比较．西南核物理与化 学研究所内部资料．
53． Karika Z，Pal I，Tarjan G，et al．Radioactive Samarium Complexes(153_Sm-EDTA and,153_Sm-DTPA)in Medical Scintigraphy．Proc IAEA Symp：Medical Radioisotope Scintigraphy 1972 IAEA-SM-164/51，Monte Cario October 23-28，1972．
54． Maxon HR，Schrode LE，Hertzberg VS，et al．Rhenium-186(Sn)HEDP for Treatment of Painful Osseous Metastases：Results of a Double-lined Crossover Comparison with Placebo．J NuclMed．1991;32：1877．
55． De Klerk JMH，Van Dijk A，Van Het Schip AD，et al．Pharmacokinetics of Rhenium-186 Afte Administration of Rhenium-186-HEDP to Patients with Bone metastases．J Nucl Med．1992； 33：646．
56． 王连生，韩朔睽．分子结构、性质与活性．化学工业出版社，1997． 8北京．
57． 罗顺忠，谯健，蒲满飞，等．153_Sm-EDTMP 在羟基棱磷灰石上的吸附．核技术．1996; 19：236．
58． 王文进，谯健，罗顺忠，等．Re-MDP 氧化态与制备条件的关系研究．西南核物理与化学 研究所待发表材料．
59． Hwang LLY,Ronca N，Solomon NA，et al．Extraction of Tc(V)from Radiophaceuticals． lnt Appl Radiat lsot．1984；35：825．
60． 张锦明，田嘉禾，杨志，等．增加188_Re-HEDP 骨摄取的方法．第七届全国放射性药物与 标记化合物学术会议．1998年，宁波．
61． 张亚东，陆洁，吕恭序．188Re-AEDP 的标记条件研究及小鼠体内分布．同位素.1998;11： 205．
62． Chilton HM，Francis MD，Thrall JH，et al．In Pharmaceuticals in Medical Imaging；Swanson DP,Chilton HM，Thrall JH．Eds；Macmillan Publishing Co．：New York，1990；pp537-563．
63． Zhida C，Tong C，Jiang B，et al．Density Functional Theory Study on the Relative Stability and Equivalence of Ligand Replacement in Rhenium Polyhydride Compounds[ReH_x(PR_3) _y]n-(x=9，y=O，n=2；x=7，5，3，y=2，3，4，n=O)．J Mole Strut．1999；466：187．
64． Feng Y, and Zhida C．Magnetic Coupling Constants and Spin Density Maps for Heterobinuclear Complexes GdCu(OTf)_3(bdmap)_2(H_2o).THF, [Gd(C_4H_7ON)_4(H_O)_3] [Fe(CN)_6] .2H_2O，and [Gd(C_4H_7ON)_4(H_2O)_3] [Cr(CN)_6] .2H_2O：A density Functional study．J Phys Chem A．2000；104：26．
65． Lixin Y, Zaiyou Qingjiang L，et al．A Computer Simulation of Infrared Spectra of Epristeride and its Analogues．首届 MSI，MDL 用户研讨会论文集(材料科学)．2000年，北 京．
66． Andrew R．Leach．Molecular Modeling：Principle and Application．Addison Wesley Longman Limited．First Edition，1996，London．
67． Rouschias G．Recent Advance in the Chemistry of Rhenium．Chem Rev．1974；74：531．
68． Jurisson S，Berning D，Jia W, et al．Coordination Compounds in Nuclear Medicine．Chem Rev． 1993；93：1137．
