CN102311458A - <99m>TcO-nucleus-labeled chlorambucil complex as well as preparing and separating and purifying methods and application thereof - Google Patents

<99m>TcO-nucleus-labeled chlorambucil complex as well as preparing and separating and purifying methods and application thereof Download PDF

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CN102311458A
CN102311458A CN201110145424A CN201110145424A CN102311458A CN 102311458 A CN102311458 A CN 102311458A CN 201110145424 A CN201110145424 A CN 201110145424A CN 201110145424 A CN201110145424 A CN 201110145424A CN 102311458 A CN102311458 A CN 102311458A
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tco
mark
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林建国
邱玲
程文
罗世能
薛丽
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Jiangsu Institute of Nuclear Medicine
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Jiangsu Institute of Nuclear Medicine
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Abstract

The invention relates to a <99m>TcO-nucleus-labeled chlorambucil complex as well as preparing and separating and purifying methods and an application thereof, and belongs to the fields of radiopharmaceutical label synthesis and application. The preparation method of the complex comprises mixing and reacting ligand N2S2-CLB, a reducer, EDTA (ethylene diamine tetraacetic acid), GH (growth hormone), phosphate buffer and sodium pertechnetate (Na<99m>TcO4) solution to obtain the <99m>TcO-nucleus-labeled chlorambucil complex. The labeled product is purified by extracting with ethyl acetate, and the purity of the purified product can reach more than 99% measured by virtue of HPLC (high performance liquid chromatography). The <99m>TcO-nucleus-labeled chlorambucil complex provided by the invention has the advantages that the preparation method is simple and easy to operate, the reaction condition is mild, and the product purity is high after separation and purification, thereby laying the excellent foundation for the subsequent research of nuclear medicine tumor imaging.

Description

A kind of 99mThe TV class title complex of TcO nuclear mark, its preparation separation purification method and uses thereof
Technical field
A kind of 99mThe TV class title complex of TcO nuclear mark, its preparation separation purification method and uses thereof belong to radiopharmaceuticals preparation and Application Areas.
Background technology
Malignant tumour is the common disease and the frequently-occurring disease of serious threat human health and life; Become human second dead reason; Be only second to cardiovascular and cerebrovascular diseases, some place risen to first reason (Zheng Hu etc. pharmaceutical chemistry. [M], Beijing: People's Health Publisher; 2001, the four editions).According to statistics, have 1/3rd people to suffer from cancer in their different steps of life course in the developed country approximately, wherein nearly 1/4th patient finally dies from cancer.It has constituted huge threat to the mankind, is the mankind's one of the most ticklish chronic diseases.
The discovery of nitrogen mustard derivatives antitumor action is considered to one of the milestone of chemotherapy of tumors development (Pratt W.B., The Anticancer Drugs. Oxford University Press, 1979).Thereafter, little in order to seek spinoff, the analogue that selectivity is high, successively synthesized 3000 surplus kind of verivate, but clinical commonly used have only 10 surplus kind.TV is one of them.The research of nitrogen mustard derivatives action principle shows, the alkanisation of mustargen is because it is the result who is cyclized into ethyleneimine under neutrality or the alkaline condition at physiological temp and pH, the nucleophilic group alkanisation of the latter and nucleic acid component and bring into play its biological action.The research proof TV in early stage has antitumor action, estimates the activation of its being selected property in tumour cell, and proof has lower toxicity and higher activity and becomes and use more a kind of alkanisation medicine afterwards clinically.
TV and other reactive group are connected, can reduce the toxicity of TV itself, and specificity also can strengthen.So people imagine two kinds of medicines be combined in may obtain in the molecule preferably active.As the physiologically active of synthetic TV verivates such as Beatrece Coggila in 2005 than two kinds of medicament mixed make and make good use of (Coggiola B., Pagliai F., et al. Bioorg. Med. Chem. Lett., 2005,15:3551).Parker L.L. in 2005 etc. have synthesized the multi-functional alkylating agent of ring-type macromole, physiologically active test shows: it and the crosslinked ability of connecing of DNA are 10 of TVs 4Doubly, be 2000 times of melphalan, its cytotoxicity and clinical medicine suitable (Parker L.L., Anderson F.M., et al. Bioorg. Med. Chem., 2005,13:2389).People such as Su T.L in 2006 with the DNA intercalator link to each other with mustargen artifact learn activity improved in various degree (Su T.L., Lin Y.W. et al. J. Med. Chem. 2006,49:3710).We are with TV and bifunctional chelating agent N in this patent 2S 2Connect through amidate action, hope to obtain labelled precursor highly sensitive to function of tumor, high specificity, and then with 99mTc passes through the ethyl acetate extraction separation and purification, pure the reaching more than 99% of finally putting of affinity tag after accomplishing mark.
At present, how detecting the generation of cancer in advance, is effectively to improve the problem that carninomatosis patient's quality of life solves emphatically.But a lot of cancer patientss can not discover oneself symptom early stage in morbidity, have delayed best treatment time, have also brought a lot of difficulties for the treatment in later stage.Also become a kind of inexorable trend so seek a kind of medicine highly sensitive, high specificity diagnosing cancer patient.
Radionuclide is in the application that medically mainly contains aspect two: the one, and nuclear medicine is used for medical diagnosis on disease; The 2nd, the radiotherapy of tumour.Nuclear medicine be exactly utilize that nuclear technique is diagnosed, a new branch of science of treatment and study of disease.And nuclear medicine is also developed rapidly as important component part in the modern age clinical medicine diagnostic imaging and CT, nucleus magnetic resonance, ultrasonic technique etc. replenish each other, and confirmation has each other improved diagnosis and treatment and research level to disease greatly.Radionuclide wherein 99mIt is very extensive that Tc uses in video picture, at first, 99mThe energy of of Tc moderate (140 KeV), the transformation period is lacked (6.02 h), is suitable for video picture; Secondly, 99mThe removing of Tc in blood is very fast, and this nucleic is by reactor production, and low price is convenient to promote the use of.TV itself is used widely as a kind of antitumor drug, with 99mCan be used as a kind of tumor developer behind the Tc mark with potential application foreground.
99mTcO-N 2S 2-CLB is that (Single-Photon Emission Computed Tomography, SPECT) developer does not have registration number to our a kind of novel tumor single photon emission computerized tomography of designing on CA, and does not have relevant report both at home and abroad yet.Expectation is through introducing bifunctional chelating agent N in the TV 2S 2And and isotropic substance 99mTc forms stable title complex, for further biological property research and tumour (malignant lymphoma, multiple myeloma, ovarian cancer, mammary cancer etc.) SPECT video picture lay the foundation.
Summary of the invention
The purpose of this invention is to provide a kind of 99mThe TV title complex of TcO nuclear mark is applied to the research and the nuclear medicine diagnostic imaging of later stage biological property, and its preparation and separation purification method is provided.
In order to solve the problems of the technologies described above, the invention provides following technical scheme:
Shown in a kind of structural formula 5 99mThe TV title complex of TcO nuclear mark:
Figure 2011101454243100002DEST_PATH_IMAGE001
。
To contain N 2S 2The N of-LCB 70-200ug 2S 2Ethanolic soln 0.1 mL of-LCB contains the EDTA-2Na aqueous solution 250 uL of EDTA-2Na 1.50-3.50 mg, 10-30 mg GH solid and contain 0.1-0.6 mg SnCl 2SnCl 22H 2O hydrochloric acid soln 0.1 mL joins in the reaction vessel, and it is fresh to add 37-55.5 MBq again 99mTcO 4 -Leacheate uses phosphate buffered saline buffer to transfer to pH and is 5-7, and the control total reaction volume is 1.5-2 mL, fully shakes mixing, and 80-100 ℃ of reaction 30 min-1.5 h promptly get mark rate greater than 81% 99mThe TV title complex of TcO mark.Said phosphate buffered saline buffer pH approximates 6, by the NaH of 0.2 mol/L 2PO 4The Na of (like 87.7 mL) and 0.2 mol/L 2HPO 4(like 12.3 mL) mix, and to transfer to pH be 5-7.
Above-mentioned mark rate is greater than 81% 99mThe separation purification method of the TV title complex of TcO mark is:
With above-mentioned gained marking fluid cooling, add ethyl acetate extraction, the upper strata is for containing affinity tag 99mTcO-N 2S 2The ETHYLE ACETATE organic layer of-CLB is isolated the ETHYLE ACETATE organic layer, and logical again nitrogen is removed ethyl acetate solvent, and the adding volume ratio is that saline water and the dissolve with ethanol of 1:1 gets final product 99mThe TV title complex of TcO mark, putting of HPLC is pure greater than 99%.
99mThe application of TV title complex in nuclear medicine diagnosing tumor video picture formulation preparation of TcO nuclear mark.
Beneficial effect of the present invention: 99mTcO-N 2S 2-CLB is a kind of novel tumor SPECT developer that we design, and on CA, does not have registration number, and does not also have relevant report both at home and abroad.We successfully introduce N in the antitumor drug TV 2S 2Sequestrant, and and radionuclide 99mTc forms stable title complex.Is 99% through a kind of easy purification process with pure the lifting by 81% of putting, and is enough to satisfy clinical in radiopharmaceutic requirement (putting is pure greater than 90%).For further biological property research and tumour (malignant lymphoma, multiple myeloma, ovarian cancer, mammary cancer etc.) video picture application is laid a good foundation.
Description of drawings
Accompanying drawing is used to provide further understanding of the present invention, and constitutes the part of specification sheets, is used to explain the present invention with embodiments of the invention, is not construed as limiting the invention.In the accompanying drawings:
Fig. 1 is the mass spectrum of the gained compound 2 of embodiment 1;
Fig. 2 is the mass spectrum of the gained compound 3 of embodiment 1;
Fig. 3 is the gained of embodiment 1 99mTcO-N 2S 2The pure HPLC of putting of-CLB measures collection of illustrative plates, and a is a water HPLC collection of illustrative plates before the affinity tag purifying for the HPLC collection of illustrative plates of free technetium, b, and c is the HPLC collection of illustrative plates behind the affinity tag ethyl acetate extraction purifying.
Embodiment
Below in conjunction with accompanying drawing the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for explanation and explains the present invention, and be not used in qualification the present invention.
) preparation 99m TcO-N 2 S 2 -CLB
Embodiment 1
Synthetic route is following:
Figure 2011101454243100002DEST_PATH_IMAGE002
(1.1)In the there-necked flask of 150 mL, add 3.04 g (0.01 mol) TV solid 1With 50 mL CH 2Cl 2In, stirring and dissolving.Slow dripping thionyl chloride under ice bath (3 g, 0.25 mol) CH 2Cl 2Solution.Stir and drip a dry DMF down.2 hours stopped reaction of room temperature reaction.Rotary evaporation is removed CH 2Cl 2, get brown oil.Mass-spectrometric data (dissolve with methanol brown oil): ESI-MS, m/z (%): 318 (100)=M-H, as shown in Figure 1.
(1.2)In 150 mL there-necked flasks, add 2(0.01 mol) and 50 mL CH 2Cl 2, stirring and dissolving.Slowly drip N under the room temperature respectively 2S 2The CH of (0.008 mol) and triethylamine (0.8 mL) 2Cl 2(20 mL) solution.Be added dropwise to complete back room temperature reaction 4 hours.Add 50 mL water and extinguish reaction, tell organic layer, use 50 mL, 0.5 mol/L HCl in succession, water, NaHCO 3Solution washing.Organic layer is used anhydrous Na 2SO 4Dry.And remove CH with rotary evaporation 2Cl 2, get yellow oil.Cross silicagel column ( V(methylene dichloride): V(ETHYLE ACETATE): V(triethylamine)=6:2:0.1) separates obtaining yellow oil.Mass-spectrometric data is (the yellow look oily matter of dissolve with methanol): ESI-MS, m/z (%): 719 (100)=M+H, and as shown in Figure 2.
1H-NMR (400 MHz, CDCl 3, ppm) resolve to: 7.20-7.33 (m, 4H, LCB-Ar), 7.05-7.09 (m, 2H, N 2S 2-Ar), 6.84-6.9 (m, 4H, N 2S 2-Ar), 6.61-6.7 (m, 2H, N 2S 2-Ar), 3.808-3.891 (m, 10H, 2O-CH 3, 2S-CH 2-Ar), 3.616-3.742 (m, 8H, 2CH 2CH 2Cl), 3.363-3.406 (m, 4H, 2CH 2-N), 2.515-2.619 (m, 4H, 2S-CH 2), 2.210-2.318 (m, 2H, CH2-CO), 1.916-1.952 (2H, CH 2), 2.089 (2H, CH 2).
(1.3)Under 0 ℃, get 0.45 g (0.63 mmol) 3Be dissolved in the trifluoroacetic acid of 5 mL, add 0.26 mL methyl-phenoxide, 0.403 g (1.26 mmol) mercuric acetate, stir 30 min under the mixture room temperature, concentrate, obtain brown thickness oily matter, vacuum-drying 30 min.Add 15 mL anhydrous diethyl ethers, stir 10 min, ultrasonic 5 min, the ether that inclines repeats 3 times.Obtain linen pulverulent solids.Ether is removed in vacuum-drying.Be dissolved in the absolute ethanol of 5 mL, feed about 30 min of hydrogen sulfide in the reaction, solution becomes black suspension.The centrifugal HgS deposition of removing, supernatant concentration gets light yellow oil and inflated with nitrogen low-temperature storage.
(1.4)In 10 mL cillin bottles, add N 2S 2Ethanolic soln 0.1 mL of-CLB (contains N 2S 2-CLB 70 ug), the EDTA-2Na aqueous solution 250 uL (containing EDTA-2Na 3.50mg), 10mg GH solid and SnCl 22H 2O hydrochloric acid soln 0.1 mL (contains 0.6mg SnCl 2), it is fresh to add 37 MBq again 99mTcO 4 -Leacheate, using phosphate buffer soln to transfer to pH is 7 and to control total reaction volume be 1.5 mL, fully shake mixing, 90-100 ℃ of reaction 30 min, mark rate is 82% 99mThe TV title complex of TcO mark.
Above-mentioned mark rate is 82% 99mThe separation purification method of the TV title complex of TcO mark is: with above-mentioned gained marking fluid cooling, add ethyl acetate extraction, the upper strata is for containing affinity tag 99mTcO-N 2S 2The ETHYLE ACETATE organic layer of-CLB is isolated the ETHYLE ACETATE organic layer, and logical again nitrogen is removed ethyl acetate solvent, and the adding volume ratio is that saline water and the dissolve with ethanol of 1:1 gets final product 99mThe TV title complex of TcO mark.
Embodiment 2
Step 1.1,1.2,1.3 is with embodiment 1, and wherein the method for step 1.4 is:
(1.4) in 10 mL cillin bottles, add N 2S 2Ethanolic soln 0.1 mL of-CLB (contains N 2S 2-CLB 200 ug), the EDTA-2Na aqueous solution 250 uL (containing EDTA-2Na 1.50mg), 30mg GH solid and SnCl 22H 2O hydrochloric acid soln 0.1 mL (contains 0.1mg SnCl 2), it is fresh to add 55.5 MBq again 99mTcO 4 -Leacheate, using phosphate buffer soln to transfer to pH is 5 and to control total reaction volume be 2 mL, fully shake mixing, 80-90 ℃ of reaction 1.5 h, mark rate is 84% 99mThe TV title complex of TcO mark.
Above-mentioned mark rate is 84% 99mThe separation purification method of the TV title complex of TcO mark is: with above-mentioned gained marking fluid cooling, add ethyl acetate extraction, the upper strata is for containing affinity tag 99mTcO-N 2S 2The ETHYLE ACETATE organic layer of-CLB is isolated the ETHYLE ACETATE organic layer, and logical again nitrogen is removed ethyl acetate solvent, and the adding volume ratio is that saline water and the dissolve with ethanol of 1:1 gets final product 99mThe TV title complex of TcO mark.
Embodiment 3
Step 1.1,1.2,1.3 is with embodiment 1, and wherein the method for step 1.4 is:
(1.4) adding contains N in 10 mL cillin bottles 2S 2The N of-LCB 140ug 2S 2Ethanolic soln 0.1 mL of-LCB contains the EDTA-2Na aqueous solution 250 uL of EDTA-2Na 2.50 mg, 20 mg GH solids and contain 0.4 mg SnCl 2SnCl 22H 2O hydrochloric acid soln 0.1 mL, it is fresh to add 46 MBq again 99mTcO 4 -Leacheate, using phosphate buffer soln to transfer to pH is 6, and the control total reaction volume is 1.8 mL, fully shakes mixing, 90-95 ℃ of reaction 1 h promptly gets mark rate and is 86% 99mThe TV title complex of TcO mark.
Above-mentioned mark rate is 86% 99mThe separation purification method of the TV title complex of TcO mark is: with above-mentioned gained marking fluid cooling, add ethyl acetate extraction, the upper strata is for containing affinity tag 99mTcO-N 2S 2The ETHYLE ACETATE organic layer of-CLB is isolated the ETHYLE ACETATE organic layer, and logical again nitrogen is removed ethyl acetate solvent, and the adding volume ratio is that saline water and the dissolve with ethanol of 1:1 gets final product 99mThe TV title complex of TcO mark.
2) 99m TcO-N 2 S 2 The mensuration that putting of-CLB is pure
99mTcO-N 2S 2-CLB mark rate is meant N technetium-99 m labeled in the system 2S 2The radioactivity of-CLB title complex accounts for the per-cent of gross activity in the system.We measure with HPLC: chromatographic column: SiineChrom ODS-BP (4.6 mm * 150 mm, 10 μ m, special company of Dalian Erie).Moving phase: V(volume(tric)fraction is 0.06% phosphoric acid solution, transfers pH to 6.0 with triethylamine): V(acetonitrile)=65: 35, flow velocity 1.0 ml/min.Detect wavelength 254 nm, 25 ℃ of column temperatures, sensitivity 0.02AUFS.HPLC equipment: Waters 600-type HPLC (U.S. Waters company) UV-detector (Waters 2487), HPLC pump (Waters 1525) radioactive detector Cd (Te) detector (U.S. Perkin Elmer company).
Under above-mentioned chromatographic condition, contain three kinds of radioactive substances without the affinity tag water that extracts, RT is respectively 3.21,3.81 and 16.20, and wherein 3.81 places are responseless free technetiums, and 16.20 places do 99mTcO-N 2S 2-CLB affinity tag, 3.21 places infer to be the GH affinity tag.Only contain a kind of radioactively labelled substance behind the ethyl acetate extraction, RT is 16.10, the result shows: when with behind the ethyl acetate extraction 99mTcO-N 2S 2The putting of-CLB is pure greater than 99%, and embodiment 1-3 is followed successively by 99.3%, 99.45% and 99.6%, is enough to satisfy the research of follow-up biological property and the requirement of tumour SPECT video picture.The HPLC collection of illustrative plates of embodiment 3 is shown in a of Fig. 3, b, c.
What should explain at last is: the above is merely the preferred embodiments of the present invention; Be not limited to the present invention; Although the present invention has been carried out detailed explanation with reference to previous embodiment; For a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment put down in writing, and perhaps part technical characterictic wherein is equal to replacement.All within spirit of the present invention and principle, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.

Claims (4)

1. shown in the structural formula 5 99mThe TV title complex of TcO nuclear mark:
Figure DEST_PATH_IMAGE001
。
2. claim 1 is described 99mThe compound method of the TV title complex of TcO nuclear mark is characterized in that: will contain N 2S 2The N of-LCB 70-200 ug 2S 2Ethanolic soln 0.1 mL of-LCB contains the EDTA-2Na aqueous solution 250 uL of EDTA-2Na 1.50-3.50 mg, 10-30 mg GH solid and contain 0.1-0.6 mg SnCl 2SnCl 22H 2O hydrochloric acid soln 0.1 mL joins in the reaction vessel, and it is fresh to add 37-55.5 MBq again 99mTcO 4 -Leacheate is used phosphate buffer soln, and the control total reaction volume is 1.5-2 mL, fully shakes mixing, and 80-100 ℃ of reaction 30 min-1.5 h promptly get mark rate greater than 81% 99mThe TV title complex of TcO mark.
3. according to claim 2 99mThe compound method of the TV title complex of TcO nuclear mark, it is characterized in that: said mark rate is greater than 81% 99mThe separation purification method of the TV title complex of TcO mark is, with the cooling of claim 2 gained marking fluid, adds ethyl acetate extraction, and the upper strata is for containing affinity tag 99mTcO-N 2S 2The ETHYLE ACETATE organic layer of-CLB is isolated the ETHYLE ACETATE organic layer, and logical again nitrogen is removed ethyl acetate solvent, and the adding volume ratio is that saline water and the dissolve with ethanol of 1:1 gets final product 99mThe TV title complex of TcO mark, putting of HPLC is pure greater than 99%.
4. claim 1-3 is described 99mThe application of TV title complex in nuclear medicine diagnosing tumor video picture formulation preparation of TcO nuclear mark.
CN201110145424A 2011-05-31 2011-05-31 <99m>TcO-nucleus-labeled chlorambucil complex as well as preparing and separating and purifying methods and application thereof Pending CN102311458A (en)

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US20010029019A1 (en) * 2000-03-27 2001-10-11 Waldman Scott A. Compositions and methods for identifying and targeting cancer cells of alimentary canal origin
CN101156953A (en) * 2007-11-16 2008-04-09 江苏省原子医学研究所 A preparation method of memantine bi-sulfur bi-nitrogen derivates medicinal box marking by technetium

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Title
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Application publication date: 20120111