CN101851313A - 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 PDFInfo
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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
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) title complex and its production and application.
Background technology
ASGP acceptor (Asialoglycoprotein receptor, ASGP-R) be writing a Chinese character in simplified form of asialoglycoprotein sugar albumin acceptor, 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 proteins 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 semi-lactosi structure all is positioned on terminal second in most of plasma proteins, therefore after terminal sugar is by enzymolysis, just can be used as the effect substrate of ASGP acceptor with the glycoprotein of semi-lactosi ending.Asialoglycoprotein glycoprotein is in case in cell surface and ASGP receptors bind, the rapid internalization of formed ligand-receptor mixture, enter about 5 minutes behind the prelysosome vesica owing to the effect of pH is dissociated, acceptor is recycled to plasma membrane, most of part is through the effect of lysosomal enzyme and the metabolism that is decomposed, the small portion part is then walked around lysosomal degraded and is entered bile, or passes cytolemma and return cell surface and still combine with acceptor.This process can be kept the running balance of plasma glycoprotein.The ASGP acceptor can reflect effective hepatocyte function to a certain extent, and when liver injury diseases such as hepatitis, liver cirrhosis or liver cancer 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 semi-lactosi structure and human serum albumin coupling obtain new lactose albumin (galactosyl-neoglycoalbumin, NGA), and warp
99mCarry out liver imaging research behind the Tc mark.Kubota in 1986 etc. have developed a kind of
99mTc mark 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 truly, digitizing reflect liver function, so both can carry out correct assessment to liver function before the liver cirrhosis patient art, aid forecasting operation risk, formulation treatment plan, the peri-operation period mortality ratio of reduction operation on liver.
Poly-(N-vinyl benzyl-D-lactose amide) compound (poly-N-p-vinylbenzyl-D-lactonamide) has good avidity to the ASGP acceptor, 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) compound with the iodine-125 mark, and it has very high avidity to the ASGP acceptor, 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 albumin such as Tc-GSA as molecular skeleton modify, mark.But 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 polymkeric substance 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 title complex 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 title complex, its expression formula is:
99mTc-PVLA, the ligand structure general formula is:
With
99mTc is a centronucleus, and part is for containing the polymkeric substance of 6-hydrazino pyridine-3-carbonylamino group (HYNIC) and semi-lactosi group---poly-(N-vinyl benzyl-D-lactose amide)-(N-vinyl benzyl-6-hydrazino pyridine-3-methane amide) (p (VLA-co-VNI));
The ratio of m and n is 1: 99～30: 70 in the formula, and diazanyl is selected phenyl aldehyde (R=C for use
6H
5), 4-dimethylaminobenzaldehyde (R=4-NMe
2-C
6H
4), phenyl aldehyde-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-hydroxyethyl) glycine (Bicine) or N-(2-hydroxyethyl)-ethylene nitrilotriacetic acid(NTA) (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 title complex is as follows:
When not using collaborative part, with poly-(N-vinyl benzyl-D-lactose amide)-(N-vinyl benzyl-6-hydrazino pyridine-3-methane amide) (p (VLA-co-VNI)) is part, prepared in reaction obtains the technetium-99 m labeled poly N-vinyl benzyl of radioactivity-D-lactose amide title complex in the presence of common part, reductive agent, and its preparation process is:
A. p (VLA-co-VNI) part is dissolved in the damping fluid; 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-hydroxyethyl) glycine (Bicine) or N-(2-hydroxyethyl)-ethylene nitrilotriacetic acid(NTA) (HEDTA);
B. be that 1: 1～800 weight ratio takes by weighing reductive agent and is dissolved in the hydrochloric acid soln by reductive agent than part then; Join in the step a gained solution, mix, control its pH between 5.5～6.5;
C. will be from medical
99Mo-
99mThe pertechnetate that drip washing obtains in the Tc producer
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 tagged compound is carried out purifying 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 phenyl aldehyde, 4-dimethylaminobenzaldehyde, phenyl aldehyde-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-hydroxyethyl) glycine (Bicine) or N-(2-hydroxyethyl)-ethylene nitrilotriacetic acid(NTA) (HEDTA), its molecular structural formula is:
Participate in coordinate small molecules part when part is technetium-99 m labeled altogether, preferably the part consumption is altogether: 20mg～100mg;
Damping fluid described in the above-mentioned steps a is: 0.05mol/L pH6.0 phosphoric acid buffer, consumption are 0.1mL～5mL;
Reductive 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 reductive 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 mark.
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-methane amide) (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; Reductive agent is 1: 1～800 weight ratio than part.
Reagent such as the common part described in the above-mentioned preparation method, damping fluid, reductive 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-methane amide) (p (VLA-co-VNI)) is part, with tricine be altogether part, collaborative part, reductive agent in the presence of prepared in reaction obtain the technetium-99 m labeled poly N-vinyl benzyl of radioactivity-D-lactose amide title complex, its preparation process is:
A. p (VLA-co-VNI) part is dissolved in the damping fluid; 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 reductive agent and is dissolved in the hydrochloric acid soln by reductive agent than part then; Join in the step b gained solution, mix, control its pH between 5.5～6.5;
D. will be from medical
99Mo-
99mDrip washing obtains in the Tc producer
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 tagged compound is carried out purifying 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 phenyl aldehyde, 4-dimethylaminobenzaldehyde, phenyl aldehyde-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:
Participate in coordinate small molecules unidentate ligand when collaborative part is technetium-99 m labeled, preferably collaborative part consumption is: 1mg～10mg;
Damping fluid described in the above-mentioned steps a is: 0.05mol/L pH6.0 phosphoric acid buffer, consumption are 0.1mL～5mL;
Reductive 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 mark.
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-methane amide) (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; Reductive agent is 1: 1～800 weight ratio than part.
Reagent such as the common part described in the above-mentioned preparation method, collaborative part, damping fluid, reductive 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-methane amide) (p (VLA-co-VNI)) part, be aided with N-three (methylol) methylglycine (Tricine), N, a kind of in N-(2-hydroxyethyl) glycine (Bicine) or N-(2-hydroxyethyl)-ethylene nitrilotriacetic acid(NTA) (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 reductive 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 title complex (
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 title complex 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 title complex 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 title complex is as follows:
1.
99mTc (PVLA) (tricine)
2Bio distribution in the normal mouse body
Get 25 normal Kunming small white mouses, 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 evaluation 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)
2.
99mTc (PVLA) (tricine)
2In the mouse body, suppress experiment
Get with batch 5 normal Kunming small white mouses, in tail vein preform injection 0.1mL inhibitor (NGA is dissolved in physiological 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 acceptor had affinity.
Table 2.
99mTc (PVLA) (tricine)
2In the normal mouse body, suppress experimental data
(5min after the injection, %ID/g ± sd, n=5)
Above-mentioned every description of test, technetium-99 m labeled poly N-vinyl benzyl of the present invention-D-lactose amide title complex (
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 liver cell receptor developer, and the interference can reduce the liver function quantitative evaluation time, can be used as novel liver cell asialoglycoprotein receptor developer
99mTc-PVLA has high chemical stability and good bio distribution character as novel title complex, can be used as liver cell acceptor SPECT developer and applies clinically.
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 title complex:
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, resistates is dissolved in chloroform, successively sodium hydroxide solution and the water with 0.2N cleans, be spin-dried for organic phase after, obtain product N-(4-vinyl benzyl)-phthalic imidine.Recrystallization in methyl alcohol.mp107-108℃。
18.4g (0.07mol) N-(4-vinyl benzyl)-phthalic imidine 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 stirring backflow 90min.Filtering-depositing, mother liquor 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 salt of wormwood drying, remove and desolvate, pressure distillation (72-73 ℃/3mmHg).
2.N-the preparation of vinyl benzyl-D-lactose amide (VLA)
Take by weighing the 1.27g lactobionic acid, add 25mL methyl alcohol, revolve behind the dispersing and dissolving to steam to remove and desolvate.Add 25mL methyl alcohol 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 methyl alcohol refluxes, will be dissolved in the 3.75mL methyl alcohol vinyl aminotoluene 0.7g (5mmol) and add reaction flask.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 methyl alcohol.
3.N-the preparation of vinyl benzyl-6-hydrazino pyridine-3-methane amide (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 succinimide 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 phenyl aldehyde, 4-dimethylaminobenzaldehyde, phenyl aldehyde-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-succinimide-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-methane amide) (p (VLA-co-VNI))
VLA and VNI are dissolved among the DMSO in 95: 5 ratio, add Diisopropyl azodicarboxylate (AIBN) (by the amount of monomeric substance 0.5%).Vacuumize and seal under the low temperature.60 ℃ of reaction 16h.Pour in the cold methyl alcohol, light-yellow precipitate occurs.To precipitate water-soluble after, the 48h that in the dialysis band of 5000MWcut, dialyses, lyophilize.
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 phosphoric acid 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 -Elutriant 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 (phosphoric acid buffer of 0.05mol/L pH 7.5) balance, is controlled flow velocity between 1～10mL/min.The 0.25mL mark 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 rate of recovery＞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
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 phosphoric acid 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 -Elutriant 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 (phosphoric acid buffer of 0.05mol/L pH 7.5) balance, is controlled flow velocity between 1～10mL/min.The 0.25mL mark 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 rate of recovery＞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 phosphoric acid 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 -Elutriant 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 (phosphoric acid buffer of 0.05mol/L pH 7.5) balance, is controlled flow velocity between 1～10mL/min.The 0.25mL mark 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 rate of recovery＞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 phosphoric acid 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 -Elutriant 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 (phosphoric acid buffer of 0.05mol/L pH 7.5) balance, is controlled flow velocity between 1～10mL/min.The 0.25mL mark 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 rate of recovery＞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 phosphoric acid 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 -Elutriant 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 (phosphoric acid buffer of 0.05mol/L pH 7.5) balance, is controlled flow velocity between 1～10mL/min.The 0.25mL mark 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 rate of recovery＞95%
99mTc (PVLA) is (TPPTS) solution (tricine).
Claims (7)
1. technetium-99 m labeled poly N-vinyl benzyl-D-lactose amide title complex, its expression formula is:
99mTc-PVLA, the ligand structure general formula is:
With
99mTc is a centronucleus, and part is the polymkeric substance that contains 6-hydrazino pyridine-3-carbonylamino group and semi-lactosi group---poly N-vinyl benzyl-D-lactose amide-N-vinyl benzyl-6-hydrazino pyridine-3-methane amide;
The ratio of m and n is 1: 99～30: 70 in the formula, and diazanyl is selected R=C for use
6H
5Phenyl aldehyde, R=4-NMe
2-C
6H
44-dimethylaminobenzaldehyde, R=2-NaO
3S-C
6H
4Phenyl aldehyde-2-sodium sulfonate or R=4-HO
2C-C
6H
4The 4-carboxyl benzaldehyde, protect by becoming hydrazone reaction; Altogether part is selected from N-trishydroxymethyl methylglycine, N, a kind of in N-2-hydroxyethyl glycine or the N-2-hydroxyethyl-ethylene nitrilotriacetic acid(NTA); When using the conduct of N-trishydroxymethyl methylglycine to be total to part, can select the collaborative part of a kind of conduct in three 3-sulfonyl-phenyl phosphine sodium salts or the triphenylphosphine list sulfonic acid list sodium salt for use.
2. as claimed in claim 1
99mPoly N-vinyl benzyl-D-the lactose amide of Tc mark) title complex is characterized in that: in described poly N-vinyl benzyl-D-lactose amide-N-vinyl benzyl-6-hydrazino pyridine-3-methane amide part, the scope of m: n is 4: 96～15: 85.
3. prepare as claimed in claim 1
99mThe preparation method of the poly N-vinyl benzyl of Tc mark-D-lactose amide title complex may further comprise the steps:
A. poly N-vinyl benzyl-D-lactose amide-N-vinyl benzyl-6-hydrazino pyridine-3-methane amide part is dissolved in the damping fluid; Is 1: 5～1000 weight ratio according to part than common part, adds part N-trishydroxymethyl methylglycine, N altogether, a kind of in N-(2-hydroxyethyl) glycine or the N-2-hydroxyethyl-ethylene nitrilotriacetic acid(NTA);
B. be 1: 2～10 weight ratio according to collaborative part than common part, a kind of in part three 3-sulfonyl-phenyl phosphine sodium salts or the triphenylphosphine list sulfonic acid list sodium salt worked in coordination with in adding;
C. be that 1: 1～800 weight ratio takes by weighing reductive agent and is dissolved in the hydrochloric acid soln by reductive agent than part then; Join in the step b gained solution, mix, control its pH between 5.5～6.5;
D. will be from medical
99Mo-
99mThe pertechnetate that drip washing obtains in the Tc producer
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 tagged compound is carried out purifying by gel chromatographic columns.
4. as described in the claim 3
99mThe preparation method of the poly N-vinyl benzyl of Tc mark-D-lactose amide title complex is characterized in that: the described reductive agent of step c is SnCl
22H
2O.
5. as described in the claim 3
99mThe preparation method of the poly N-vinyl benzyl of Tc mark-D-lactose amide title complex is characterized in that: the described reactant reaction time of steps d is 20 minutes.
6. as described in the claim 3
99mThe preparation method of the poly N-vinyl benzyl of Tc mark-D-lactose amide title complex is characterized in that: described reductive agent: part: the weight ratio of part is 1: 20: 2500 altogether.
7. as described in the claim 3
99mThe preparation method of the poly N-vinyl benzyl of Tc mark-D-lactose amide title complex is characterized in that: the consumption of the described poly N-vinyl benzyl of step a-D-lactose amide-N-vinyl benzyl-6-hydrazino pyridine-3-methane amide part is 0.1mg～4mg; Described arbitrary consumption of part altogether is: 20mg～100mg.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892820A (en) * | 2015-05-11 | 2015-09-09 | 厦门大学 | Receptor-like molecular targeted developing agent and preparation method therefor |
| CN105669785A (en) * | 2016-03-16 | 2016-06-15 | 中国科学院高能物理研究所 | 99mTc marked multivalence sugar fan-shaped dendrimer complex, application thereof, multivalence sugar fan-shaped dendrimer ligand and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2909881A1 (en) * | 2006-12-14 | 2008-06-20 | Inst Nat Sante Rech Med | NOVEL CONJUGATES FOR USE IN THERAPEUTIC PURPOSES AND / OR AS DIAGNOSTIC AND / OR IMAGING AGENTS AND METHOD FOR PREPARING THE SAME |
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| FR2909881A1 (en) * | 2006-12-14 | 2008-06-20 | Inst Nat Sante Rech Med | NOVEL CONJUGATES FOR USE IN THERAPEUTIC PURPOSES AND / OR AS DIAGNOSTIC AND / OR IMAGING AGENTS AND METHOD FOR PREPARING THE SAME |
Non-Patent Citations (1)
| Title |
|---|
| 《北京师范大学学报(自然科学版)》 20030630 张现忠等 不同中心核锝99m标记CPeI配合物的制备与生物分布 全文 1-7 , 第03期 2 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892820A (en) * | 2015-05-11 | 2015-09-09 | 厦门大学 | Receptor-like molecular targeted developing agent and preparation method therefor |
| CN105669785A (en) * | 2016-03-16 | 2016-06-15 | 中国科学院高能物理研究所 | 99mTc marked multivalence sugar fan-shaped dendrimer complex, application thereof, multivalence sugar fan-shaped dendrimer ligand and preparation method thereof |
| CN105669785B (en) * | 2016-03-16 | 2018-01-19 | 中国科学院高能物理研究所 | 99mThe fan-shaped tree-shaped molecular complex of multivalence sugar of Tc marks and its purposes and the fan-shaped dendrimer ligands of multivalence sugar and its preparation method |
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