CN101851313B - Technetium-99m-marked poly N-vinyl benzyl-D-lactose amide composition and preparation method - Google Patents

Technetium-99m-marked poly N-vinyl benzyl-D-lactose amide composition and preparation method Download PDF

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CN101851313B
CN101851313B CN2010101748011A CN201010174801A CN101851313B CN 101851313 B CN101851313 B CN 101851313B CN 2010101748011 A CN2010101748011 A CN 2010101748011A CN 201010174801 A CN201010174801 A CN 201010174801A CN 101851313 B CN101851313 B CN 101851313B
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vinyl benzyl
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technetium
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张现忠
杨文江
王学斌
陆洁
张俊波
唐志刚
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BEIJING SHIHONG PHARMACEUTICAL RESEARCH CENTER
Beijing Normal University
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Beijing Normal University
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Abstract

The invention discloses a technetium-99m-marked poly N-vinyl benzyl-D-lactose amide composition. By using 99mTc as a central core, using polymer-poly N-vinyl benzyl-D-lactose amide-N-vinyl benzyl-6-hydrazino pyridine-3-formamide containing 6-hydrazino pyridine-3-formamide groups and galactose groups as a ligand, adopting one of N-tris hydroxymethyl-methylglycine, N,N-2-hydroxyethyl glycine and N-2-hydroxyethyl ethylene diaminetriacetic acid as a common ligand and adopting one of tris(3-sulfonatophenyl) phosphine hydrate or tris(3-sulfonatophenyl) phosphine sodium salt as a synergetic ligand, the technetium-99m-marked poly N-vinyl benzyl-D-lactose amide composition is prepared through the steps of mixing, reduction, reaction, purification and the like. The composition has the advantages of good chemical stability and biological performance, high specific activity, high liver uptake value and target to non-target ratio, simple preparation and low operating cost and can be used for preparing novel liver receptor developers applied in the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine.

Description

Technetium-99 m labeled poly N-vinyl benzyl-D-lactose amide coordination compound and preparation method
Affiliated technical field
The present invention relates to technetium-99 m labeled radiopharmaceutical chemistry and clinical nuclear medicine technical field, particularly relate to a kind of technetium-99 m labeled poly-(N-vinyl benzyl-D-lactose amide) coordination compound and its production and application.
Background technology
ASGP receptor (Asialoglycoprotein receptor, ASGP-R) be writing a Chinese character in simplified form of asialoglycoprotein sugar albumin receptor, being present on the hepatocyte of mammal film, is asialoglycoprotein glycoprotein (Asialoglycoprotein, single-minded site ASGP) in the mediation hepatic clearance blood.Nearly all plasma protein all is a glycoprotein except albumin, and when being synthesized by liver and being discharged into blood, its sugar-chain end is a sialic acid.Sialic acid forms more weak being connected with other glycosyl, and is also unstable in blood, very easy being eliminated.Sialic acid partly is eliminated, and indicates the end in this glycoprotein life-span.The galactose structure all is positioned on terminal second in most of plasma protein, therefore after terminal sugar is by enzymolysis, just can be used as the effect substrate of ASGP receptor with the glycoprotein of galactose ending.The asialoglycoprotein glycoprotein is in case in cell surface and ASGP receptors bind, the rapid internalization of formed ligand-receptor complex, enter about 5 minutes behind the prelysosome vesicle owing to the effect of pH is dissociated, receptor is recycled to plasma membrane, most of part is through the effect of lysosomal enzyme and the metabolism that is decomposed, the fraction part is then walked around lysosomal degraded and is entered bile, or passes cell membrane and return cell surface and still combine with receptor.This process can be kept the dynamic equilibrium of plasma glycoprotein.The ASGP receptor can reflect effective hepatocyte function to a certain extent, and when hepatic injury diseases such as hepatitis, liver cirrhosis or hepatocarcinoma took place, its quantity and activity all suffered damage.Hepatitis disease worldwide all is a kind of disease occurred frequently, and particularly liver cirrhosis secondary liver cancer patient is numerous, has a strong impact on human health and quality of life, and its importance has caused that now extensive concern appears suddenly.Vera in 1984 etc. by chemical synthesis process with galactose structure and human serum albumin's coupling obtain new lactose albumin (galactosyl-neoglycoalbumin, NGA), and warp 99mCarry out liver imaging research behind the Tc labelling.Kubota in 1986 etc. have developed a kind of 99mTc labelling GSA ( 99mTc-diethylenetriamine pentaaceticacid-galactosyl-human serum albumin),, simplified flag condition, reduced non-specific binding by increasing bifunctional linking reagent DTPA (diethylene triamine pentacetic acid (DTPA)) structure.Japan has utilized the ASGPR developer to set up three-dimensional hepatic model for nuclear medicine liver SPECT video picture, this imaging technique can be truly, digitized ground reflection liver function, so both can carry out correct assessment to liver function before the liver cirrhosis patient art, aid forecasting operation risk, formulation therapeutic scheme, the peri-operation period mortality rate of reduction operation on liver.
Poly-(N-vinyl benzyl-D-lactose amide) chemical compound (poly-N-p-vinylbenzyl-D-lactonamide) has good affinity to the ASGP receptor, and is main at present with being a kind of liver tissue engineering scaffold material of synthetic.Goto in 1994 etc. have reported poly-(N-vinyl benzyl-D-lactose amide) chemical compound with the iodine-125 labelling, and it has very high affinity to the ASGP receptor, has preferably in liver and concentrates.Technetium-99m is the modal radionuclide of present clinical use, has good nucleic character.At present technetium-99 m labeled ASGP receptor developer as 99mEmploying human serum albumins such as Tc-GSA as molecular skeleton modify, labelling.But the human serum albumin is apt to deteriorate, is difficult for preserving.Finding a kind of good stability, can be used for the SPECT developer that technetium-99 m labeled artificial polymer exploitation is used for liver ASGP rii receptor is the important topic that the present technique field need solve.
Summary of the invention
The purpose of this invention is to provide a kind ofly have that chemical stability is strong, biological property good, initial picked-up value and chemical purity height, preparation is simple and use cost is low, is applied in the technetium-99 m labeled poly N-vinyl benzyl-D-lactose amide coordination compound in liver receptor SPECT video picture field.And provide its preparation method.
In order to achieve the above object, the present invention by the following technical solutions: a kind of technetium-99 m labeled poly N-vinyl benzyl-D-lactose amide coordination compound, its expression formula is: 99mTc-PVLA, the ligand structure general formula is:
Figure BSA00000128676400021
With 99mTc is a centronucleus, and part is for containing the polymer of 6-hydrazino pyridine-3-carbonylamino group (HYNIC) and galactose group---poly-(N-vinyl benzyl-D-lactose amide)-(N-vinyl benzyl-6-hydrazino pyridine-3-Methanamide) (p (VLA-co-VNI));
The ratio of m and n is 1: 99～30: 70 in the formula, and diazanyl is selected benzaldehyde (R=C for use 6H 5), 4-dimethylaminobenzaldehyde (R=4-NMe 2-C 6H 4), benzaldehyde-2-sodium sulfonate (R=2-NaO 3S-C 6H 4) or 4-carboxyl benzaldehyde (R=4-HO 2C-C 6H 4) protect by becoming hydrazone reaction.Altogether part is selected from N-three (methylol) methylglycine (Tricine), N, a kind of in N-(2-ethoxy) glycine (Bicine) or N-(2-ethoxy)-ethylene nitrilotriacetic acid (HEDTA); When using the conduct of N-three (methylol) methylglycine to be total to part, can select the collaborative part of a kind of conduct in three (3-sulfonyl-phenyl) phosphine sodium salts (TPPTS) or the triphenylphosphine list sulfonic acid list sodium salt (TPPMS) for use.
In the preferred part of the present invention, the ratio of m and n is 4: 96～15: 85.
The preparation method of technetium-99 m labeled poly N-vinyl benzyl-D-lactose amide coordination compound is as follows:
When not using collaborative part, with poly-(N-vinyl benzyl-D-lactose amide)-(N-vinyl benzyl-6-hydrazino pyridine-3-Methanamide) (p (VLA-co-VNI)) is part, prepared in reaction obtains the technetium-99 m labeled poly N-vinyl benzyl of radioactivity-D-lactose amide coordination compound in the presence of common part, Reducing agent, and its preparation process is:
A. p (VLA-co-VNI) part is dissolved in the buffer; 's 1: 5～1000 weight ratio according to part than common part, add part N-three (methylol) methylglycine (Tricine), N altogether, a kind of in N-(2-ethoxy) glycine (Bicine) or N-(2-ethoxy)-ethylene nitrilotriacetic acid (HEDTA);
B. be that 1: 1～800 weight ratio takes by weighing Reducing agent and is dissolved in the hydrochloric acid solution by Reducing agent than part then; Join in the step a gained solution, mix homogeneously is controlled its pH between 5.5～6.5;
C. will be from medical 99Mo- 99mThe pertechnetate that drip washing obtains in the Tc generator 99mTcO 4 -Leacheate adds in the solution of step b preparation, and reacted under the boiling water bath condition 10～100 minutes the sealing back;
D. step c gained labelled compound is carried out purification by gel chromatographic columns.
The consumption of preferred p (VLA-co-VNI) part is 0.1mg～4mg among the above-mentioned steps a;
Diazanyl can select for use benzaldehyde, 4-dimethylaminobenzaldehyde, benzaldehyde-2-sodium sulfonate or 4-carboxyl benzaldehyde etc. to protect in p among the above-mentioned steps a (VLA-co-VNI) part, to increase the stability of part; The diazanyl blocking group dissociates when heating in step c, the diazanyl behind the deprotection with 99mThe coordination of Tc centronucleus.
Described in the above-mentioned steps a altogether part be N-three (methylol) methylglycine (Tricine), N, a kind of in N-(2-ethoxy) glycine (Bicine) or N-(2-ethoxy)-ethylene nitrilotriacetic acid (HEDTA), its molecular structural formula is:
Participate in coordinate micromolecule part when part is technetium-99 m labeled altogether, preferably the part consumption is altogether: 20mg～100mg;
Buffer described in the above-mentioned steps a is: 0.05mol/L pH6.0 phosphate buffer, consumption are 0.1mL～5mL;
Reducing agent described in the above-mentioned steps b is: general's high price technetium ( 99mTc VIIO 4 -) be reduced to the at a low price conventional chemical reagent of technetium: two hydrated stannous chloride (SnCl 22H 2O), preferred Reducing agent consumption is: 0.005mg～0.1mg;
Among the above-mentioned steps c, the blocking group hydrolysis of diazanyl is left away in the part, makes diazanyl expose out, thereby carries out labelling.
It is the gel column (HiTrap Desalting gel column) of sephadex G 25 (Sephadex G25) that gel chromatographic columns described in the above-mentioned steps d is selected filler for use;
Poly-(N-vinyl benzyl-D-lactose amide)-(N-vinyl benzyl-6-hydrazino pyridine-3-Methanamide) (p (VLA-co-VNI)) part described in the above-mentioned preparation method is for synthetic voluntarily, and its preferred part consumption is 0.1mg-4mg.Part is 1: 5～1000 weight ratio than common part; Reducing agent is 1: 1～800 weight ratio than part.
Reagent such as the common part described in the above-mentioned preparation method, buffer, Reducing agent are all to buy from market.
When part is worked in coordination with in use, with poly-(N-vinyl benzyl-D-lactose amide)-(N-vinyl benzyl-6-hydrazino pyridine-3-Methanamide) (p (VLA-co-VNI)) is part, with tricine be altogether part, collaborative part, Reducing agent in the presence of prepared in reaction obtain the technetium-99 m labeled poly N-vinyl benzyl of radioactivity-D-lactose amide coordination compound, its preparation process is:
A. p (VLA-co-VNI) part is dissolved in the buffer; Is 1: 5～1000 weight ratio according to part than common part, adds part N-three (methylol) methylglycine (Tricine) altogether;
B. be 1: 2～10 weight ratio according to collaborative part than common part, part is worked in coordination with in adding;
C. be that 1: 1～800 weight ratio takes by weighing Reducing agent and is dissolved in the hydrochloric acid solution by Reducing agent than part then; Join in the step b gained solution, mix homogeneously is controlled its pH between 5.5～6.5;
D. will be from medical 99Mo- 99mDrip washing obtains in the Tc generator 99mTcO 4 -Leacheate adds in the solution of step c preparation, and reacted under the boiling water bath condition 10～100 minutes the sealing back;
E. steps d gained labelled compound is carried out purification by gel chromatographic columns.
The consumption of preferred p (VLA-co-VNI) part is 0.1mg～4mg among the above-mentioned steps a;
Diazanyl can select for use benzaldehyde, 4-dimethylaminobenzaldehyde, benzaldehyde-2-sodium sulfonate or 4-carboxyl benzaldehyde to protect in p among the above-mentioned steps a (VLA-co-VNI) part, to increase the stability of part; The diazanyl blocking group dissociates when heating in steps d, the diazanyl behind the deprotection with 99mThe coordination of Tc centronucleus.
Being total to part described in the above-mentioned steps a is N-three (methylol) methylglycine (Tricine), and preferably the part consumption is altogether: 20mg～100mg;
Collaborative part described in the above-mentioned steps b is a kind of in three (3-sulfonyl-phenyl) phosphine sodium salts (TPPTS) or the triphenylphosphine list sulfonic acid list sodium salt (TPPMS), and its molecular structural formula is:
Figure BSA00000128676400051
Collaborative part participates in coordinate micromolecule monodentate ligand when being technetium-99 m labeled, preferably collaborative part consumption is: 1mg～10mg;
Buffer described in the above-mentioned steps a is: 0.05mol/L pH6.0 phosphate buffer, consumption are 0.1mL～5mL;
Reducing agent described in the above-mentioned steps c is: general's high price technetium ( 99mTc VIIO 4 -) be reduced to the at a low price conventional chemical reagent of technetium: two hydrated stannous chloride (SnCl 22H 2O), preferred former dose of consumption is: 0.005mg-0.1mg;
Among the above-mentioned steps d, the blocking group hydrolysis of diazanyl is left away in the part, makes diazanyl expose out, thereby carries out labelling.
It is the gel column (HiTrap Desalting gel column) of sephadex G 25 (Sephadex G25) that gel chromatographic columns described in the above-mentioned steps e is selected filler for use;
Poly-(N-vinyl benzyl-D-lactose amide)-(N-vinyl benzyl-6-hydrazino pyridine-3-Methanamide) (p (VLA-co-VNI)) part described in the above-mentioned preparation method is for synthetic voluntarily, and its preferred part consumption is 0.1mg～4mg.Part is 1: 5～1000 weight ratio than common part; Collaborative part is 1: 2～10 weight ratio than common part; Reducing agent is 1: 1～800 weight ratio than part.
Reagent such as the common part described in the above-mentioned preparation method, collaborative part, buffer, Reducing agent are all to buy from market.
The present invention with radiopertechnetate ( 99mTcO 4 -) and poly-(N-vinyl benzyl-D-lactose amide)-(N-vinyl benzyl-6-hydrazino pyridine-3-Methanamide) (p (VLA-co-VNI)) part, be aided with N-three (methylol) methylglycine (Tricine), N, a kind of in N-(2-ethoxy) glycine (Bicine) or N-(2-ethoxy)-ethylene nitrilotriacetic acid (HEDTA) is part altogether; When using the conduct of N-three (methylol) methylglycine to be total to part, can select the collaborative part of a kind of conduct in three (3-sulfonyl-phenyl) phosphine sodium salts (TPPTS) or the triphenylphosphine list sulfonic acid list sodium salt (TPPMS) for use; At Reducing agent SnCl 22H 2Under the existence of O, prepared in reaction obtain the technetium-99 m labeled poly N-vinyl benzyl of a kind of radioactivity-D-lactose amide coordination compound ( 99mTc-PVLA), chemical stability and biological property are good, specific activity is high, liver picked-up value and target to non-target ratio value height, preparation is simple and use cost is low, can be used to prepare novel liver receptor developer.
Detection shows: the technetium-99 m labeled poly N-vinyl benzyl-D-lactose amide coordination compound of gained identifies by thin layer chromatography and HPLC, and its radiochemical purity is greater than 99%, and at room temperature places radiochemicsl purity no change after 4 hours, and stability is preferably arranged.
To use tricine among the embodiment 1 for being total to the coordination compound that part obtains 99mTc (PVLA) (tricine) 2Be example, experiment shows that the basic performance of technetium-99 m labeled poly N-vinyl benzyl-D-lactose amide coordination compound is as follows:
1. 99mTc (PVLA) (tricine) 2Bio distribution in the normal mouse body
Get 25 normal Kunming white mice, in tail vein injection 0.1mL 99mTc (PVLA) (tricine) 2(about 0.185MBq contains 1 μ g PVLA).Sacrificed by decapitation behind injection back 5,10,30,60 and 120min.Take out tissues such as the heart, liver, lung, kidney, muscle, bone, blood, weighing is also surveyed its radiocounting in gamma counter.
99mTc (PVLA) (tricine) 2Bio distribution in normal mouse sees Table 1.
Bio distribution result's demonstration in normal mouse, 99mTc (PVLA) (tricine) 2Very high initial picked-up is arranged in liver, behind the injection 5min, the picked-up value of (125.33 ± 10.99) %ID/g is arranged in liver.Radioactivity at non-target organs such as the heart, lung, kidney, spleens concentrates lower.Particularly radioactivity in blood, the kidney concentrates and is starkly lower than present clinical use 99mTc-GSA, this quantitative assessment for the liver position has great importance.Based on above bio distribution experimental result, 99mTc (PVLA) (tricine) 2Show good biological property, helped in the video picture in future, enough obtaining more distinct image and data more accurately.
Table 1. 99mTc (PVLA) (tricine) 2Bio distribution data in the normal mouse body (%ID/g ± sd, n=5)
Figure BSA00000128676400071
2. 99mTc (PVLA) (tricine) 2In the mice body, suppress experiment
Get with batch 5 normal Kunming white mice, in tail vein preform injection 0.1mL inhibitor (NGA is dissolved in normal saline, presses the dosage injection of 10mg/kg body weight), behind the 5min, in tail vein injection 0.1mL 99mTc (PVLA) (tricine) 2(about 0.185MBq contains 1 μ g PVLA).Sacrificed by decapitation behind the 5min of injection back.Take out tissues such as the heart, liver, lung, kidney, muscle, bone, blood, weighing is also surveyed its radiocounting in the technetium analyser.
99mTc (PVLA) (tricine) 2In the normal mouse body, suppress experimental result and see Table 2.
Suppress result of experiment and show, passing through preform injection NGA, can obvious suppression when 5min 99mTc (PVLA) (tricine) 2Picked-up in mouse liver (P＜0.001) does not in a large number enter liver 99mTc (PVLA) (tricine) 2Be trapped in the blood, also obviously increase in each internal organs picked-up such as the heart, lung, kidney.
Suppress the result of experiment explanation by preform injection NGA, can effectively suppress 99mTc (PVLA) (tricine) 2Picked-up in liver.Proof 99mTc (PVLA) (tricine) 2The ASGP receptor had affinity.
Table 2. 99mTc (PVLA) (tricine) 2In the normal mouse body, suppress experimental data
(5min after the injection, %ID/g ± sd, n=5)
Figure BSA00000128676400081
Above-mentioned every description of test, technetium-99 m labeled poly N-vinyl benzyl of the present invention-D-lactose amide coordination compound ( 99mTc-PVLA), radiochemical purity has very high chemical stability greater than 99%.Have good biological property, higher initial picked-up is arranged in liver; With 99mTc-GSA compares lower non-target internal organs picked-up, satisfy condition, can reduce unnecessary radiation injury as the hepatocyte receptor developer, and the interference can reduce the liver function quantitative assessment time, can be used as novel hepatocyte asialoglycoprotein receptor developer 99mTc-PVLA has high chemical stability and good bio distribution character as novel coordination compound, can be used as hepatocyte receptor SPECT developer and applies clinically.
The specific embodiment:
Below by embodiment in detail the present invention is described in detail, a kind of technetium-99 m labeled poly N-vinyl benzyl-D-lactose amide coordination compound:
1. synthetic to the vinyl aminotoluene
4-1-chloro-4-methyl-benzene 15.3g (0.10mol) and potassium phthalimide 18.5g (0.10mol) are dissolved among the 50mL DMF, are heated to 50 ℃ of reaction 4h.Revolve to steam and remove DMF, residue is dissolved in chloroform, successively sodium hydroxide solution and the water with 0.2N cleans, be spin-dried for organic facies after, obtain product N-(4-vinyl benzyl)-phthalimide.Recrystallization in methanol.mp107-108℃。
18.4g (0.07mol) N-(4-vinyl benzyl)-phthalimide is dissolved in the 50mL ethanol, reflux is added dropwise to the hydrazine hydrate 6.6g (0.105mol) that is dissolved in 10mL alcoholic acid 80%.White precipitate appears immediately, mechanical agitation backflow 90min.Filtering-depositing, mother solution is spin-dried for solvent, after solid is merged, be dissolved in KOH solution (20gKOH, 120mLH2O).Merge ether with extracted with diethyl ether (140mL * 1,70mL * 4) and wash (40mL * 4) with 2% solution of potassium carbonate mutually, after the potassium carbonate drying, remove and desolvate, distillation under pressure (72-73 ℃/3mmHg).
2.N-the preparation of vinyl benzyl-D-lactose amide (VLA)
Take by weighing the 1.27g lactobionic acid, add 25mL methanol, revolve behind the dispersing and dissolving to steam to remove and desolvate.Add 25mL methanol again, revolve behind the dispersing and dissolving to steam to remove and desolvate.Repeat 20 times.Obtain the lactobionic acid lactone.
Lactose lactone 1.7g (5mmol) is dissolved in the 17mL methanol refluxes, will be dissolved in the 3.75mL methanol vinyl aminotoluene 0.7g (5mmol) and add reaction bulb.Back flow reaction 120min is cooled to room temperature, produces white crystal.After the filtration, solid is washed vacuum drying with a spot of cold methanol.
3.N-the preparation of vinyl benzyl-6-hydrazino pyridine-3-Methanamide (VNI)
6-hydrazino pyridine-3-formic acid (HYNIC) 1g (6.5mmol) is dissolved among the 40mLDMF, and the aldehydes of amounts such as adding carries out diazanyl protection, stirring at room 3h.Add butanimide 748mg (6.5mmol) and DCC2.76g (13.4mmol), room temperature reaction 18h.Filter, filtrate is spin-dried for, and adds the 50mL ethyl acetate, reflux 1h, and heat filtering obtains yellow powder.
The aldehydes that is added can be protected diazanyl by becoming hydrazone reaction, can select benzaldehyde, 4-dimethylaminobenzaldehyde, benzaldehyde-2-sodium sulfonate or 4-carboxyl benzaldehyde etc. for use.Blocking group is left away by heating hydrolysis in labeling process, carries out coordination thereby diazanyl is exposed.
N-butanimide-6-hydrazino pyridine-3-formic acid and vinyl aminotoluene were fed intake room temperature reaction 24h in DMF by 1.2: 1.Revolve to steam to remove and desolvate, respectively with obtaining buff powder after ethyl acetate and the methanol wash.
4. the preparation of poly-(N-vinyl benzyl-D-lactose amide)-(N-vinyl benzyl-6-hydrazino pyridine-3-Methanamide) (p (VLA-co-VNI))
VLA and VNI are dissolved among the DMSO in 95: 5 ratio, add azodiisobutyronitrile (AIBN) (by the amount of monomeric substance 0.5%).Evacuation and sealing under the low temperature.60 ℃ of reaction 16h.Pour in the cold methanol, light-yellow precipitate occurs.To precipitate water-soluble after, the 48h that in the dialysis band of 5000MWcut, dialyses, lyophilization.
Embodiment 1:
With Tricine as part altogether, 99mTc (PVLA) (tricine) 2Preparation:
Get p (VLA-co-VNI) 0.2mg and be dissolved in the 0.5mL phosphate buffer (0.05mol/L pH6.0 contains 30mg part tricine altogether), treat that all the dissolving back adds 2mg/mL SnCl 22H 2O solution 10 μ L fully shake up.Add fresh at last 99mTcO 4 -Eluent 0.5mL (37MBq), fully vibration, 20min is reacted in the sealing back in boiling water bath.Promptly obtain 99mTc (PVLA) (tricine) 2
HiTrap desalination gel column (Sephadex G25) with 25mL leacheate (phosphate buffer of 0.05mol/L pH 7.5) balance, is controlled flow velocity between 1～10mL/min.The 0.25mL labelling is good 99mTc (PVLA) (tricine) 2With sample on the 1mL syringe, with after the drip washing of 1.25mL leacheate, collect the 1mL leacheate earlier, the impurity that is removed, the response rate＞95% 99mTc (PVLA) (tricine) 2Solution.
Identify that by chromatography and RP-HPLC its retention time is 11.9min, radiochemical purity is greater than 99%.The HPLC condition is: high performance liquid chromatograph SHIMADZU (SCL-10Avp); Kromaisl C4 post 250 * 4.6mm, 5 μ m
Figure BSA00000128676400101
A is water (containing 0.1%TFA) mutually, and B is acetonitrile (containing 0.1%TFA) mutually; The drip washing gradient is: 0～5min:5%B phase, 5～30min:30%～70%B phase; Flow velocity 1mL/min.
Embodiment 2:
With Bicine as part altogether, 99mTc (PVLA) preparation (bicine):
Get p (VLA-co-VNI) 1mg and be dissolved in the 0.5mL phosphate buffer (0.05mol/L pH6.0 contains 20mg part bicine altogether), treat that all the dissolving back adds 2mg/mL SnCl 22H 2O solution 5 μ L fully shake up.Add fresh at last 99mTcO 4 -Eluent 0.5mL (37MBq), fully vibration, 20min is reacted in the sealing back in boiling water bath.Promptly obtain 99mTc (PVLA) (bicine).
HiTrap desalination gel column (Sephadex G25) with 25mL leacheate (phosphate buffer of 0.05mol/L pH 7.5) balance, is controlled flow velocity between 1～10mL/min.The 0.25mL labelling is good 99mTc (PVLA) (bicine) with sample on the 1mL syringe, with after the drip washing of 1.25mL leacheate, collects the 1mL leacheate earlier, the impurity that is removed, the response rate＞95% 99mTc (PVLA) is solution (bicine).
Embodiment 3:
With HEDTA as part altogether, 99mTc (PVLA) preparation (HEDTA):
Get p (VLA-co-VNI) 3mg and be dissolved in the 0.5mL phosphate buffer (0.05mol/L pH6.0 contains 50mg part HEDTA altogether), treat that all the dissolving back adds 2mg/mL SnCl 22H 2O solution 20 μ L fully shake up.Add fresh at last 99mTcO 4 -Eluent 0.5mL (37MBq), fully vibration, 20min is reacted in the sealing back in boiling water bath.Promptly obtain 99mTc (PVLA) (HEDTA).
HiTrap desalination gel column (Sephadex G25) with 25mL leacheate (phosphate buffer of 0.05mol/L pH 7.5) balance, is controlled flow velocity between 1～10mL/min.The 0.25mL labelling is good 99mTc (PVLA) (HEDTA) with sample on the 1mL syringe, with after the drip washing of 1.25mL leacheate, collects the 1mL leacheate earlier, the impurity that is removed, the response rate＞95% 99mTc (PVLA) is solution (HEDTA).
Embodiment 4:
As being total to part, part is worked in coordination with in the TPPMS conduct with Tricine, 99m(tricine) preparation of (TPPMS) of Tc (PVLA):
Get p (VLA-co-VNI) 0.1mg and be dissolved in the 0.5mL phosphate buffer (0.05mol/L pH6.0 contains 25mg part tricine altogether, and 5mg works in coordination with part TPPMS), treat that all the dissolving back adds 2mg/mL SnCl 22H 2O solution 5 μ L fully shake up.Add fresh at last 99mTcO 4 -Eluent 0.5mL (37MBq), fully vibration, 20min is reacted in the sealing back in boiling water bath.Promptly obtain 99mTc (PVLA) is (TPPMS) (tricine).
HiTrap desalination gel column (Sephadex G25) with 25mL leacheate (phosphate buffer of 0.05mol/L pH 7.5) balance, is controlled flow velocity between 1～10mL/min.The 0.25mL labelling is good 99mTc (PVLA) (tricine) (TPPMS) with after the drip washing of 1.25mL leacheate, collects the 1mL leacheate earlier with sample on the 1mL syringe, the impurity that is removed, the response rate＞95% 99mTc (PVLA) is (TPPMS) solution (tricine).
Embodiment 5:
As being total to part, part is worked in coordination with in the TPPTS conduct with Tricine, 99m(tricine) preparation of (TPPTS) of Tc (PVLA):
Get p (VLA-co-VNI) 0.5mg and be dissolved in the 0.5mL phosphate buffer (0.05mol/L pH6.0 contains 30mg part tricine altogether, and 3mg works in coordination with part TPPTS), treat that all the dissolving back adds 2mg/mL SnCl 22H 2O solution 5 μ L fully shake up.Add fresh at last 99mTcO 4 -Eluent 0.5mL (37MBq), fully vibration, 20min is reacted in the sealing back in boiling water bath.Promptly obtain 99mTc (PVLA) is (TPPTS) (tricine).
HiTrap desalination gel column (Sephadex G25) with 25mL leacheate (phosphate buffer of 0.05mol/L pH 7.5) balance, is controlled flow velocity between 1～10mL/min.The 0.25mL labelling is good 99mTc (PVLA) (tricine) (TPPTS) with after the drip washing of 1.25mL leacheate, collects the 1mL leacheate earlier with sample on the 1mL syringe, the impurity that is removed, the response rate＞95% 99mTc (PVLA) is (TPPTS) solution (tricine).

Claims (5)

1. the preparation method of technetium-99 m labeled poly N-vinyl benzyl-D-lactose amide coordination compound, this method is as follows:
When not using collaborative part, with poly-(N-vinyl benzyl-D-lactose amide)-(N-vinyl benzyl-6-hydrazino pyridine-3-Methanamide) (p (VLA-co-VNI)) is part, prepared in reaction obtains the technetium-99 m labeled poly N-vinyl benzyl of radioactivity-D-lactose amide coordination compound in the presence of common part, Reducing agent, and its preparation process is:
A. p (VLA-co-VNI) part is dissolved in the buffer; 's 1: 5～1000 weight ratio according to part than common part, add N-three (methylol) methylglycine (Tricine), N, a kind of conduct in N-(2-ethoxy) glycine (Bicine) or N-(2-ethoxy)-ethylene nitrilotriacetic acid (HEDTA) is part altogether;
Diazanyl selects for use benzaldehyde, 4-dimethylaminobenzaldehyde, benzaldehyde-2-sodium sulfonate or 4-carboxyl benzaldehyde to protect in p among the above-mentioned steps A (VLA-co-VNI) part, to increase the stability of part;
B. be that 1: 1～800 weight ratio takes by weighing Reducing agent and is dissolved in the hydrochloric acid solution by Reducing agent than part then; Join in the step a gained solution, mix homogeneously is controlled its pH between 5.5～6.5, and wherein Reducing agent is two hydrated stannous chlorides;
C. will be from medical 99Mo- 99mThe pertechnetate that drip washing obtains in the Tc generator 99mTcO 4 -Leacheate adds in the solution of step b preparation, and reacted under the boiling water bath condition 10～100 minutes the sealing back, dissociate when wherein the diazanyl blocking group heat in step c, the diazanyl behind the deprotection and 99mThe coordination of Tc centronucleus;
D. step c gained labelled compound is carried out purification by gel chromatographic columns;
When part is worked in coordination with in use, with poly-(N-vinyl benzyl-D-lactose amide)-(N-vinyl benzyl-6-hydrazino pyridine-3-Methanamide) (p (VLA-co-VNI)) is part, with N-three (methylol) methylglycine be altogether part, collaborative part, Reducing agent in the presence of prepared in reaction obtain the technetium-99 m labeled poly N-vinyl benzyl of radioactivity-D-lactose amide coordination compound, its preparation process is:
A. p (VLA-co-VNI) part is dissolved in the buffer; Is 1: 5～1000 weight ratio according to part than common part, adds part N-three (methylol) methylglycine altogether;
Diazanyl selects for use benzaldehyde, 4-dimethylaminobenzaldehyde, benzaldehyde-2-sodium sulfonate or 4-carboxyl benzaldehyde to protect in p among the above-mentioned steps a (VLA-co-VNI) part, to increase the stability of part;
B. be 1: 2～10 weight ratio according to collaborative part than common part, add and work in coordination with part that wherein working in coordination with part is three (3-sulfonyl-phenyl) phosphine sodium salts or triphenylphosphine list sulfonic acid list sodium salt;
C. be that 1: 1～800 weight ratio takes by weighing Reducing agent and is dissolved in the hydrochloric acid solution by Reducing agent than part then; Join in the step b gained solution, mix homogeneously is controlled its pH between 5.5～6.5, and wherein Reducing agent is two hydrated stannous chlorides;
D. will be from medical 99Mo- 99mDrip washing obtains in the Tc generator 99mTcO 4 -Leacheate adds in the solution of step c preparation, and reacted under the boiling water bath condition 10～100 minutes the sealing back, and the diazanyl blocking group dissociates when heat in steps d, the diazanyl behind the deprotection and 99mThe coordination of Tc centronucleus;
E. steps d gained labelled compound is carried out purification by gel chromatographic columns.
2. the described method of claim 1, wherein step is characterized in that: the described response time of step C and d is 20 minutes.
3. the preparation method of technetium-99 m labeled according to claim 1 poly N-vinyl benzyl-D-lactose amide coordination compound is characterized in that: described Reducing agent: part: the weight ratio of part is 1: 20: 2500 altogether.
4. the preparation method of technetium-99 m labeled according to claim 1 poly N-vinyl benzyl-D-lactose amide coordination compound is characterized in that: the consumption of the described poly N-vinyl benzyl of steps A and a-D-lactose amide-N-vinyl benzyl-6-hydrazino pyridine-3-Methanamide part is 0.1mg～4mg; Described arbitrary consumption of part altogether is: 20mg～100mg.
5. the technetium-99 m labeled poly N-vinyl benzyl-D-lactose amide coordination compound of the described method of claim 1 preparation.
CN2010101748011A 2010-05-17 2010-05-17 Technetium-99m-marked poly N-vinyl benzyl-D-lactose amide composition and preparation method Expired - Fee Related CN101851313B (en)

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