CN101654465B - Caobonyl technetium labeled 2-azomycin composition, preparation method and application - Google Patents
Caobonyl technetium labeled 2-azomycin composition, preparation method and application Download PDFInfo
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Abstract
The invention discloses a radioactive nuclide labeled compound which is caobonyl technetium labeled 2-azomycin composition, a preparation method of the compound and a purpose of the compound. The preparation method of the caobonyl technetium labeled 2-azomycin composition comprises the following steps: firstly synthesizing a ligand NC-PEGn-NIM and heating the ligand and a newly prepared midbody 99mTc(CO)3(H2O)3+, the pH value of which is regulated to 9 to 10, to obtain the caobonyl technetium labeled 2-azomycin composition. The caobonyl technetium labeled 2-azomycin composition is concentrated in anoxybiotic tumor cells by the targeting function of azomycin and can be used for the SPECT raster display diagnosis of anoxybiotic tumors.
Description
Technical field
The present invention relates to one type of compound with radioisotope labeling, and the preparation method of this compound and purposes, specifically involved in the present invention is technetium carbonyl marked 2-nitroimidazole complex.
Background technology
Malignant tumour is one of principal disease that causes human unusual death, on China and the global disease death rate and the cause of death, stands out.Weary oxygen is the total characteristic of humans and animals tumour, and experimental observation shows that the ratio of anoxic cell is generally 10-20% in the solid tumor with measuring, have in addition up to 50%.Treatment means to malignant tumour mainly is a radiation and chemotherapy except that operation at present, but weary oxygen causes tumor tissues insensitive to radiation and chemotherapy, has improved its resistivity to radiation and chemotherapy greatly; Simultaneously, weary oxygen makes oxygen in the tumour regulate albumen (ORP), VEGF (VEGF) over-expresses of etc.ing and makes himself aggressive increase; In addition, tumor hypoxia can also cause apoptosis and induced tumor vasculogenesis.Therefore, being determined at of tumour cell oxygen level is significant clinically, helps the early diagnosis of tumour, the definite and therapeutic evaluation of regimen.
It is the biochemistry variation in the research vital process that the radiopharmaceuticals most important applications is worth; Utilizing the small molecules of radioisotope labeling to carry out PET or SPECT video picture can live body non-invasive diagnostic various diseases, is the most active research field of molecular imaging in recent years.The tumor hypoxia developer is one type of positive developer, can optionally be trapped in hypoxic tissue or the cell, and survey histanoxia and degree thereof through nuclear medicine image, and it is one of radiopharmaceutic in recent years research focus.Ideal tumor hypoxia developer should possess following conditions: 1. have enough amount selectivity to concentrate in weary oxygen district and have certain residence time; 2. for surveying the slight change of tissue oxygen tension, the contrast of reliable healthy tissues and ischemic tissue can be provided; 3. video picture quality is high, and patient receives irradiation dose little.
The tumor hypoxia developer that has been used at present clinical study comprises
18FMISO,
99mTc-HL91,
64Cu-ATSM etc., but their clinical video picture performance is unsatisfactory, main problem comprises that the absolute picked-up of tumour is on the low side, and healthy tissues is removed slower, and liver belly radioactivity concentrates etc.Domestic and international research personnel have carried out extensive and deep research in order to obtain the excellent more tumor hypoxia developer of video picture character, have explored a series of
18F,
99mTc,
123/125I with
62/64The nitro glyoxaline of marks such as Cu or non-nitro imidazole derivatives, but regrettably these verivates are not having substantive breakthroughs aspect the clinical video picture value.Therefore study the important subject that the novel tumor anoxia developing agent with the clinical imaging results of ideal is still the present technique field.
99mTc is the desirable nucleic that is used for nuclear medicine SPECT video picture, and carbonyl technetium core is widely used in
99mThe research of Tc medicine.
Chinese patent 95108299.X discloses a kind of medical box for labelling pingyangmycin for tumer positive developing agent; This medicine adopts developer technetium [Tc-99m] mark Zhengguangmycin A5 (PYM) medicinal box special; Adopting anticarcinogen PYM, micro-tin salt, hydrochloric acid, saline water and other additives etc. is starting material; As radioactive trace, can be used for the diagnosis of nuclear medicine clinical cancer with Tc-99m.
Chinese patent 96194172.3 discloses and can be used as diagnosis of cardiovascular diseases, the new radiopharmaceuticals of infection and cancer contrast medium.This radiopharmaceuticals is made up of the bioactive molecules that phosphine or arsine combine technetium-99 m labeled hydrazine or diazine to modify, and said bioactive molecule optionally positions disease site, thereby can obtain the image in site of living in through the γ scintillography.
Chinese invention patent application 200780024367.5 discloses sijna rice glue body of a kind of mtc labeled and preparation method thereof.Said colloid mixes with the solution that contains tin or its compound, sodium or its compound, Prist and Vinylpyrrolidone polymer through the solution with radioactive technetium or its compound and prepares.
Summary of the invention
The present invention provides one type of tracer that is used for tumor hypoxia video picture medicine in other words, and the preparation method and its usage of this tracer agent.
Tracer of the present invention is technetium carbonyl marked 2-nitroimidazole complex, and its general structure is suc as formula shown in 1:
Formula 1
R is suc as formula shown in 2 in the formula 1
Formula 2
N=1 in the formula 2～10.
Technetium carbonyl marked 2-nitroimidazole complex preferably of the present invention is n=3.
Preparing method's (showing 3) of technetium carbonyl marked 2-nitroimidazole complex of the present invention is:
A. polyoxyethylene glycol and triethylamine are dissolved in the methylene dichloride; Slowly drip the solution of the methylene dichloride that is dissolved with Tosyl chloride more therein; Fully after the reaction; Suction filtration is removed solid, filtrating after washing except that desolvate the compound 1 of thick liquid nano, wherein polymerization degree n is any in 1～10;
B. with compound 1 and 2-nitroimidazole, and Na
2CO
3Join CH
3Among the CN, back flow reaction fully back gets compound 2 except that desolvating and crossing column purification with silicagel column;
C. with compound 2 and NaN
3Join among the DMF, reacting by heating, removal of solvent under reduced pressure is also crossed column purification with silicagel column, compound 3;
D. with PPh
3(triphenyl phosphorus), compound 3 and water dissolution are in THF, and fully the reaction back is removed and desolvated, and crosses column purification with silicagel column, gets compound 4;
E. compound 4 is dissolved in ethyl formate, the fully reaction that refluxes removes and desolvates, and crosses column purification with silicagel column, gets compound 5;
F. under the condition of ice bath, will contain SOCl
2Anhydrous THF solution slowly be added drop-wise in the solution that compound 5 is dissolved in THF, after abundant reaction, solution is adjusted to remove after the weakly alkaline desolvates, and cross column purification with silicagel column, part NC-PEG
n-NIM;
Formula 3: the synthetic route of each midbody and 2-nitroimidazole part
G. with part NC-PEG
nThe pH value adjusted of-NIM and prepared fresh be 9～10 [
99mTc (CO)
3(H
2O)
3]
+Midbody (reference: Alberto R., Schibli R., Egli A., Schubiger, AP.J Am Chem Soc, 1998 (120), 7987-7988) reacting by heating in boiling water bath, obtain technetium carbonyl marked 2-nitroimidazole complex [
99mTc (CO)
3(NC-PEGn-NIM)
3]
+(seeing formula 1).
Used polyethylene glycol polymeric degree is 1～10 among the above preparation method.
Preparing method as the technetium carbonyl marked 2-nitroimidazole complex of most preferred embodiment of the present invention is;
A. tetraethylene-glycol 30mmol and triethylamine 90mmol are dissolved in the 30mL methylene dichloride; Slowly drip the solution that Tosyl chloride 66mmol is dissolved in methylene dichloride 30mL; Accomplish the continued room temperature reaction after 4 hours; Suction filtration is removed solid, filtrating washing after drying handle remove again desolvate the compound 1a of viscous liquid;
B. with compound 1a (15.6mmol), 2-nitroimidazole (13mmol) and Na
2CO
3(15.6mmol) join in the 50mL acetonitrile, back flow reaction except that desolvating and crossing column purification with silicagel column, gets faint yellow viscous liquid 2a;
C. with compound 2a (4.51mmol), NaN
3(5.41mmol) join among the 2mL DMF, be heated to 100 ℃ of fully reactions,, get the compound 3a of faint yellow viscous liquid except that desolvating and crossing column purification with silicagel column;
D. with PPh
3(5.35mmol), compound 3a (4.20mmol) and water 0.8g are dissolved among the 10mLTHF, 30-40 ℃ of fully reaction, except that desolvating and crossing column purification with silicagel column, get the compound 4a of light yellow oil;
E. compound 4a (0.347mmol) is dissolved in the 5mL ethyl formate, after back flow reaction is abundant,, gets the compound 5a of light yellow oil except that desolvating and crossing column purification with silicagel column;
F. under condition of ice bath, will contain 14 μ L SOCl
2The 1mL anhydrous THF solution slowly be added drop-wise to compound 5a (0.215mmol) and be dissolved in the solution of 1mL THF; Under agitation condition, continue room temperature reaction fully after; With ammoniacal liquor solution is adjusted to weakly alkaline,, gets the part NC-PEG of light yellow oil except that desolvating and crossing column purification with silicagel column
3-NIM;
G. with prepared fresh [
99mTc (CO)
3(H
2O)
3]
+Midbody solution is regulated pH=9～10, adds the NC-PEG that 0.1mL concentration is 1mg/mL more therein
3-NIM ligand solution, shake up the back in boiling water bath reacting by heating fully technetium carbonyl marked 2-nitroimidazole complex [
99mTc (CO)
3(NC-PEG
3-NIM)
3]
+(seeing formula 4).
Technetium carbonyl marked 2-nitroimidazole complex of the present invention can be in the application in the preparation tumor hypoxia developer.
The technetium carbonyl marked 2-nitroimidazole complex that the present invention relates to, on structure, the target group of such title complex is the 2-nitroimidazole, (NC) group is participated in the coordination of carbonyl technetium to three ligand moleculars through isonitrile.Polyoxyethylene glycol (PEG) is as linking group, and the change of polymerization degree n can influence the water-soluble of part and title complex, and then has influence on
99mThe pharmacokinetics of Tc marked product etc.; But it can not influence the mtc labeled performance of part, can not influence the tumor hypoxia target characteristic of 2-nitroimidazole yet; Therefore, the present invention does not have special demands to the polymerization degree n of the PEG of linking group, and the number of n can be between 1-10, and their corresponding technetium carbonyl marked products all can have close tumor characteristic, can carry out the tumor hypoxia video picture through SPECT.
Since the 2-nitroimidazole be targeting in anoxic cell biomolecules, polyoxyethylene glycol (PEG) is that a kind of drug effect of widely using is regulated group, contains three targeted moleculars in the title complex of the present invention simultaneously, therefore [
99mTc (CO)
3]
+The Pegylation of mark (PEGylated) 2-nitroimidazole complex has good tumor hypoxia cellular affinity, can improve the picked-up of tumour to medicine, reaches better localization diagnosis result.
Embodiment
Below provide a specific embodiment of the present invention, the polymerization degree n of used polyoxyethylene glycol linking group is 3 in this embodiment.
Synthesizing of Pegylation 2-nitroimidazole part
Compound 1a (Tetraethylene glycol di (p-toluenesulfonate)): with tetraethylene-glycol (5.82g, 30mmol) and triethylamine (9.1g 90mmol) is dissolved in the 30mL methylene dichloride; (12.6g 66mmol) is dissolved in the solution of methylene dichloride (30mL), accomplishes the continued room temperature reaction after 4 hours slowly to drip Tosyl chloride; Suction filtration is removed solid; Filtrating washing 4 times, the dry final vacuum of organic phase remove desolvate viscous liquid 12.67g (25.2mmol, 84%).
1H?NMR(400MHz，CDCl
3)：δ＝2.45(s，6H，OCH
3)，3.57(s，8H)，3.68(t，4H，J＝4.5Hz)，4.15(t，4H，J＝4.5Hz)，7.34(d，4H，J＝8.1Hz)，7.79(d，4H，J＝8.1Hz)，ppm.
Compound 2a (2-(2-(2-(2-(2-nitro-1H-imidazol-1-yl) ethoxy) ethoxy) ethoxy) ethyl4-methylbenzenesulfonate): with compound 1 (7.8g, 15.6mmol), the 2-nitroimidazole (1.5g, 13mmol) and Na
2CO
3(1.65g 15.6mmol) joins 50mL CH
3Among the CN, back flow reaction 15h; Revolve and do, get faint yellow viscous liquid 2.70g (6.09mmol, 46.8%) except that desolvating and crossing column purification with silicagel column.EI-MS：442(M
+)
Compound 3a (1-(2-(2-(2-(2-azidoethoxy) ethoxy) ethoxy) ethyl)-2-nitro-1H-imidazole): with compound 2a (2g, 4.51mmol) and NaN
3(351.8mg 5.41mmol) joins among the 2mL DMF, is heated to 100 ℃ of reaction 2h; Removal of solvent under reduced pressure is also crossed column purification with silicagel column, faint yellow viscous liquid 1.32g (4.20mmol, 93.1%).
1H?NMR(400?MHz，CDCl
3)：δ＝3.40(t，2H)，3.60-3.70(m，10H)，3.86(t，2H)，4.63(t，2H)，7.13(s，1H)，7.29(s，1H)，ppm.ESI-MS：315.1(MH
+)
Compound 4a (2-(2-(2-(2-(2-nitro-1H-imidazol-1-yl) ethoxy) ethoxy) ethoxy) ethanamine): with PPh
3(1.40g, 5.35mmol), compound 3a (1.32g, 4.20mmol) and water (0.8g) be dissolved among the 10mL THF, 30-40 ℃ the reaction 36 hours; Removal of solvent under reduced pressure is also crossed column purification with silicagel column, light yellow oil 1.04g (3.61mmol, 86.0%).
1H?NMR(400MHz，CDCl
3)：δ＝2.87(t，2H)，3.49-3.61(m，10H)，3.86(t，2H)，4.63(t，2H)，7.13(s，1H)，7.28(s，1H)，ppm.ESI-MS：289.1(MH
+)
Compound 5a (N-(2-(2-(2-(2-(2-nitro-1H-imidazol-1-yl) ethoxy) ethoxy) ethoxy) ethyl) formamide): with compound 4a (100mg; 0.347mmol) be dissolved in the 5mL ethyl formate; Back flow reaction 8 hours; Removal of solvent under reduced pressure is also crossed column purification with silicagel column, light yellow oil 68mg (0.215mmol, 62.0%).
1H?NMR(400?MHz，CDCl
3)：2.12(s，1H)，3.49-3.62(m，12H)，3.86(t，2H)，4.66(t，2H)，7.14(s，1H)，7.25(s，1H)，8.20(s，1H)，ppm.ESI-MS：317.2(MH
+)。
Part NC-PEG
3-NIM (1-(2-(2-(2-(2-isocyanoethoxy) ethoxy) ethoxy) ethyl)-2-nitro-1H-imidazole): under the condition of ice bath, will contain 14 μ L SOCl
2The 1mL anhydrous THF solution slowly be added drop-wise to compound 5a (68mg; 0.215mmol) be dissolved in the solution of the anhydrous THF of 1mL; Accomplished the continued room temperature reaction 3 hours, and with ammoniacal liquor solution was adjusted to weakly alkaline, removal of solvent under reduced pressure is also crossed column purification with silicagel column; Get light yellow oil 10mg (0.0335mmol, 15.6%).
1H?NMR(400MHz，CDCl
3)：3.61-3.67(m，10H)，3.76(t，2H)，3.84(t，2H)，4.20(t，2H)，7.14(s，1H)，7.28(s，1H)，ppm.ESI-MS：297.3(M-H
+)。
More than reaction is referring to formula 3.
The preparation of technetium carbonyl marked 2-nitroimidazole complex
[
99mTc (CO)
3(NC-PEG
3-NIM)
3]
+The preparation of (formula 4): with prepared fresh [
99mTc (CO)
3(H
2O)
3]
+Midbody solution is regulated pH=9～10; The NC-PEG that in a cillin bottle, adds 0.1mL 1mg/mL
3-NIM ligand solution and 0.4mL have regulated the midbody solution (10mCi) of pH value, shake up back reacting by heating 15min in boiling water bath.
Formula 4
The detection of technetium carbonyl marked 2-nitroimidazole complex
Adopt thin-layer chromatography (TLC) method to identify: with the polymeric amide thin slice is support; The expansion system is acetone/saline water=1/1, after waiting to launch to finish, the polymeric amide thin slice is divided into 10 sections; With the radiocounting of γ-each section of calculating instrument mensuration, the R of each technetium carbonyl marked 2-nitroimidazole complex
fValue between 0.4～0.7, and [
99mTc (CO)
3(H
2O)
3]
+The R of midbody
fValue is 0.
The TLC analytical results show according to the method described above preparation [
99mTc (CO)
3(NC-PEG
3-NIM)
3]
+Putting pure greater than 95%; And room temperature is placed the pure no considerable change of putting of 6h, shows that title complex has satisfactory stability property.
The lipid of technetium carbonyl marked 2-nitroimidazole complex
With n-Octanol and phosphate buffered saline buffer (25mM, pH=7.4) equal-volume mixes, and adds an amount of marker ligand compound to be measured; Behind the shake well, equal-volume organic phase and water are got in the high speed centrifugation layering; Measure the biphase radiocounting respectively; The partition ratio P of title complex to be measured is the ratio of organic phase and water radiocounting, repeatedly repeats this operation, averages.Lipid is generally represented with Log P.
Measure the result and show that title complex is water-soluble, [
99mTc (CO)
3(NC-PEG
3-NIM)
3]
+Log P value be 1.48 ± 0.34.
Distribute in the tumor-bearing mice body of technetium carbonyl marked 2-nitroimidazole complex
Lotus S180 sarcoma mouse model: implant 2 * 10 in the left front oxter of female kunming mice (the about 20-22g of body weight)
6Individual S180 tumour cell, raise about 10 days after, diameter of tumor grows to 6-10mm, quality is about 0.4-1.0g.
Through an amount of title complex to be measured of lotus S180 sarcoma mouse tail vein injection; Injection back 5,30,60,120min are with the mouse sacrificed by decapitation; Get interested organ and tissues such as its tumour, blood, the heart, liver, spleen, lung, kidney, small intestine, brain, bone, muscle; Measure its radiocounting after weighing respectively, the result representes (%ID/g) with the percentage picked-up dosage of every gram tissue or organ.
Distribution results is shown in table 1 in the tumor-bearing mice body of labeled drug.[
99mTc (CO)
3(NC-PEG
3-NIM)
3]
+Have extraordinary tumor uptake and delay, the tumor uptake (ID%/g) of injection back 5,30,60 and 120min reaches 6.02 ± 4.17,2.05 ± 0.39,2.52 ± 0.15 and 2.18 ± 0.41 respectively; Aspect target/non-target ratio, [
99mTc (CO)
3(NC-PEG
3-NIM)
3]
+Tumour/muscle relatively good, injection back 5,30,60 and 120min are respectively 11.04 ± 3.90,2.56 ± 0.87,2.04 ± 0.10 and 1.28 ± 0.60.
Table 1: [
99mTc (CO)
3(NC-PEG
3-NIM)
3]
+Distribution results in the tumor-bearing mice body (ID%/g, x ± s, n=3)
| ID％/g | 5min | 30min | 60min | 120min |
| Tumour | 6.02±4.17 | 2.05±0.39 | 2.52±0.15 | 2.18±0.41 |
| Blood | 14.57±5.05 | 5.48±0.11 | 4.39±0.36 | 4.09±0.58 |
| The heart | 5.51±0.73 | 1.38±0.10 | 2.07±0.33 | 1.71±0.48 |
| Liver | 5.85±1.50 | 3.50±0.69 | 4.39±0.24 | 4.27±0.25 |
| Spleen | 3.17±0.22 | 1.42±0.17 | 1.61±0.02 | 1.69±0.20 |
| Lung | 11.87±2.46 | 3.85±0.82 | 4.19±2.26 | 3.98±0.38 |
| Kidney | 6.89±0.85 | 5.46±0.21 | 4.47±0.40 | 5.47±1.13 |
| Small intestine | 2.40±2.60 | 1.84±0.06 | 2.62±1.11 | 2.76±0.78 |
| Brain | 0.58±0.31 | 0.24±0.09 | 0.20±0.01 | 0.21±0.02 |
| Muscle | 0.65±0.48 | 0.83±0.12 | 1.24±0.14 | 1.89±0.69 |
| Bone | 0.04±0.08 | 1.42±0.11 | 1.89±0.23 | 1.83±0.85 |
| Tumour/blood | 0.38±0.20 | 0.37±0.06 | 0.58±0.01 | 0.53±0.09 |
| Tumour/muscle | 11.04±3.90 | 2.56±0.87 | 2.04±0.10 | 1.28±0.60 |
In a word, the present invention relates to one type of novel technetium carbonyl marked 2-nitroimidazole complex and preparation method and purposes.The constructional feature of such title complex is: (1) is the target group with the 2-nitroimidazole, and targeting is in hypoxic tumor cells; (2) be that linking group carries out the drug effect adjusting with polyoxyethylene glycol PEG; (3) (NC) group is that hapto and carbonyl technetium core chelating obtain affinity tag with isonitrile; (4) there are three ligand moleculars to participate in coordination simultaneously and form title complex, increased the target avidity of title complex.The 2-nitroimidazole part compound method of the present invention's design is reliable, and the preparation of title complex is simply effective.Such technetium carbonyl marked 2-nitroimidazole complex has good water-solubility, the pure height of putting and having good stability.Distribution experiment has confirmed that all they have good tumor uptake and delay in the lotus S180 mice with tumor body.Such technetium carbonyl marked 2-nitroimidazole complex concentrates in hypoxic tumor cells through the targeting of nitroimidazole, can be used for the SPECT localization diagnosis of hypoxic tumor.
Claims (3)
1. technetium carbonyl marked 2-nitroimidazole complex, its general structure is suc as formula shown in 1:
Wherein R is suc as formula
shown in 2
N=3 in the formula 2.
2. the preparation method of a kind of technetium carbonyl marked 2-nitroimidazole complex according to claim 1 is characterized in that:
A. 30mmol tetraethylene-glycol and 90mmol triethylamine are dissolved in the 30mL methylene dichloride; Slowly drip the solution that the 66mmol Tosyl chloride is dissolved in the 30mL methylene dichloride; Accomplished the continued room temperature reaction 4 hours; Suction filtration is removed solid, filtrating washing after drying handle remove again desolvate the compound 1a of viscous liquid;
B. with 15.6mmol compound 1a, 13mmol 2-nitroimidazole and 15.6mmol Na
2CO
3Join in the 50mL acetonitrile, back flow reaction except that desolvating and crossing column purification with silicagel column, gets faint yellow viscous liquid 2a;
C. with 4.51mmol compound 2a, 5.41mmol NaN
3Join among the 2mL DMF, be heated to 100 ℃ of fully reactions,, get the compound 3a of faint yellow viscous liquid except that desolvating and crossing column purification with silicagel column;
D. with 5.35mmol PPh
3, 4.20mmol compound 3a and 0.8g water dissolution 30-40 ℃ of fully reaction, except that desolvating and crossing column purification with silicagel column, get the compound 4a of light yellow oil in 10mL THF;
E. 0.347mmol compound 4a is dissolved in the 5mL ethyl formate, after back flow reaction is abundant,, gets the compound 5a of light yellow oil except that desolvating and crossing column purification with silicagel column;
F. under condition of ice bath, will contain 14 μ L SOCl
2The 1mL anhydrous THF solution slowly be added drop-wise to 0.215mmol compound 5a and be dissolved in the solution of the anhydrous THF of 1mL; Under agitation condition, continue room temperature reaction fully after; With ammoniacal liquor solution is adjusted to weakly alkaline,, gets the part CN-PEG of light yellow oil except that desolvating and crossing column purification with silicagel column
3-NIM;
G. with prepared fresh [
99mTc (CO)
3(H
2O)
3]
+Midbody solution is regulated pH=9～10, adds the CN-PEG that 0.1mL concentration is 1mg/mL more therein
3-NIM ligand solution, shake up the back in boiling water bath sufficient reacting get technetium carbonyl marked 2-nitroimidazole complex [
99mTc (CO)
3(CN-PEG
3-NIM)
3]
+
3. the described technetium carbonyl marked 2-nitroimidazole complex of claim 1 is in the application for preparing the tumor hypoxia developer.
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|---|---|---|---|---|
| US5538712A (en) * | 1990-06-01 | 1996-07-23 | Institut Fur Diagnostikforschung Gmbh/An Der Freien Universitat Berlin | Cyclopentadienylcarbonyl 99MTC complexes, process for their production as well as their use in diagnostics |
| CN101475595A (en) * | 2009-02-17 | 2009-07-08 | 北京师范大学 | 99TcmN nuclear marker nitro glyoxaline xanthate complexes, as well as preparation method and use thereof |
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