CN101486763A - Technetium-99m marked dimercapto propionamido novel lactose albumin complexes, preparation and use thereof - Google Patents
Technetium-99m marked dimercapto propionamido novel lactose albumin complexes, preparation and use thereof Download PDFInfo
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- CN101486763A CN101486763A CNA2009100793695A CN200910079369A CN101486763A CN 101486763 A CN101486763 A CN 101486763A CN A2009100793695 A CNA2009100793695 A CN A2009100793695A CN 200910079369 A CN200910079369 A CN 200910079369A CN 101486763 A CN101486763 A CN 101486763A
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Abstract
The invention discloses a technetium-99m labeled dimercaptopropanol amido new lactose albumin complex, a preparation method and application thereof; radioactive pertechnetate (<99m>TcO4<->) is synthesized with dimercaptopropanol amido new lactose albumin into a ligand (DMP-NGA); and under the presence of reducing agent and protective agent, the radioactive technetium-99m labeled dimercaptopropanol amido new lactose albumin complex is prepared by reaction. The complex has good chemical stability and biological property, high initial uptake value and target and chemical purity, simple preparation and low use cost, and can be used in radiopharmaceuticals and clinical nuclear medicine technology field as a novel liver imaging agent.
Description
Affiliated technical field
The present invention relates to
99mThe radiopharmaceutical chemistry of Tc mark and clinical nuclear medicine technical field particularly relate to a kind of technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes 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.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.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 pentaacetic acid-galactosyl-human serum albumin),, simplified flag condition, reduced non-specific binding by increasing bifunctional linking reagent DTPA (diethylene triamine pentacetic acid (DTPA)) structure.But
99mTc-GSA still exists
99mThe Tc binding ability is lower, in the slightly high shortcoming of kidney picked-up.2004, usefulness β mercapto-ethanol reduction LSA such as Jeong (neolactosyl human serum albumin) obtained containing the part of sulfydryl, used
99mBehind the Tc mark, demonstrate stability and excellent biological property preferably, but can destroy proteinic structure, and then influence its intravital biological property by the reduction disulfide linkage.
How by introducing the dimercapto propionic acid that contains sulfydryl on the NGA molecule, when not influencing the protein molecular structure, strengthen the coordination ability of itself and technetium-99m, obtain technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes and prepare a kind of novel technetium-99 m labeled title complex the liver receptor developer, be the problem that current present technique field need solve.
Summary of the invention
The purpose of this invention is to provide good, initial picked-up value of a kind of tool chemical stability and biological property and chemical purity height, preparation is simple and use cost is low, be applied in liver receptor video picture field technetium-99 m labeled dimercapto propionamido novel lactose albumin (
99mTc-DMP-NGA) title complex.
Another object of the present invention provides preparation method and the application of a kind of described title complex as the liver receptor developer.
In order to achieve the above object, the present invention by the following technical solutions: a kind of technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes, the general structure of its ligand molecular dimercapto propionamido novel lactose albumin (DMP-NGA) is:
In the formula: DMP-NGA is that part is to connect n galactosyl and m dimercapto propionamido simultaneously by lysine residue on the human serum albumin molecular chain, and wherein n is 20-45, and m and n sum are smaller or equal to 56.
The preparation method of technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes is as follows:
With radiopertechnetate (
99mTcO
4 -) with dimercapto propionamido novel lactose albumin synthetic ligands (DMP-NGA), reductive agent, protectant in the presence of prepared in reaction obtain the technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes of described radioactivity, its preparation process is:
A. the DMP-NGA part being dissolved in the damping fluid, is the weight ratio of 1:0.2～10 according to protective material than part, adds protective material;
B. be that the weight ratio of 1:25～500 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-
99mDrip washing obtains in the Tc producer
99mTcO
4 -Leacheate adds in the solution of step b preparation, reacts 10～60min behind the mixing under 20 ℃～80 ℃ conditions;
D. step c gained solution is carried out purifying by high performance liquid chromatography.
The protective material of stating described in the above-mentioned steps a is: Seignette salt, its consumption is: 0.5mg-5mg.
Damping fluid described in the above-mentioned steps a is: 0.05mol/L pH6.0 phosphoric acid buffer, consumption are 0.1mL～5mL.
Described reductive agent described in the above-mentioned steps b is: with radiopertechnetate (
99mTcO
4 -) be reduced to
99mTc
5+Conventional chemical reagent, be preferably two hydrated stannous chloride (SnCl
22H
2O), former dose of consumption is: 0.01mg-0.04mg.
Dimercapto propionamido novel lactose albumin part described in the above-mentioned preparation method is for synthetic voluntarily, and its part consumption is 1mg-5mg; Reductive agent is the weight ratio of 1:25～500 than part, and protective material is the weight ratio of 1:0.2～10 than part.
Reagent such as the protective material described in the above-mentioned preparation method, damping fluid, reductive agent all can be buied from market.
The present invention is with radiopertechnetate
99mTc7 (
99mTc
4 -) close proportioning with dimercapto propionamido novel lactose albumin and become part (DMP-NGA), reductive agent, protectant in the presence of, prepared in reaction obtain the technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes of radioactivity (
99mTc-DMP-NGA), be a kind of novel liver cell asialoglycoprotein receptor (ASGPR) developer, by bifunctional linking reagent dimercapto propionic acid, when not influencing the protein molecular structure, in the NGA molecule, introduce sulfydryl.Compare with GSA, strengthened coordination ability with technetium-99m.
99mIt is low that good, initial picked-up value of Tc-DMP-NGA chemical stability and biological property and target and chemical purity height, preparation simply reach use cost, can become a kind of novel liver developer.
Detection shows:
99mThe Tc-DMP-NGA title complex identifies that by chromatography and RP-HPLC its radiochemical purity is greater than 98%, and radiochemicsl purity has stability preferably greater than 91% after 6 hours and at room temperature place.
Experiment shows,
99mThe basic performance of Tc-DMP-NGA title complex is as follows:
1.
99mTc-DMP-NGA is bio distribution in the normal mouse body
Get 15 normal Kunming small white mouses, in tail vein injection 0.1mL
99mTc-DMP-NGA (about 0.185MBq contains 2 μ g DMP-NGA).Sacrificed by decapitation behind injection back 5,30 and 120min.Take out tissues such as the heart, liver, lung, kidney, muscle, bone, blood, weighing is also surveyed its radiocounting in the technetium analyser.
99mThe bio distribution of Tc-DMP-NGA in normal mouse sees Table 1.
Table 1.
99mTc-DMP-NGA in the normal mouse body bio distribution data (%ID/g ± s, n=5) and with
99mTc-GSA (%ID/g ± s, n=3) contrast of biological property
Bio distribution result's demonstration in normal mouse,
99mTc-DMP-NGA has higher initial picked-up in liver, and the delay in liver is better than
99mEven Tc-GSA, still has the picked-up value of (52.47 ± 7.58) %ID/g at 120min in liver.It is lower to concentrate in the radioactivity of internal organs such as the heart, lung, spleen, with
99mTc-GSA is similar.Picked-up ratio in muscle and bone
99mTc-GSA is slightly high.But
99mTc-DMP-NGA together
99mTc-GSA compares, and the picked-up value in kidney and blood obviously reduces, and liver/kidney, liver/blood reach 14.4 and 83.4 than respectively during 30min, apparently higher than
99mLiver/the kidney of Tc-GSA when 30min, liver/blood is than (being respectively 5.7 and 31.7), such the possibility of result be because
99mThe Tc-DMP-NGA coordination is more stable, and stability in vivo better in the SPECT in future video picture, can obtain more distinct image.
2.
99mTc-DMP-NGA suppresses experiment in the mouse body
Get with batch 5 normal Kunming small white mouses, in tail vein preform injection 0.1mL inhibitor (the GSA part is dissolved in physiological saline, presses the dosage injection of 10mg/kg body weight), behind the 5min, in tail vein injection 0.1mL
99mTc-DMP-NGA (about 0.185MBq contains 2 μ g DMP-NGA).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-DMP-NGA suppresses experimental result and sees Table 2 in the normal mouse body.
Table 2.
99mTc-DMP-NGA in the normal mouse body, suppress experimental data (5min after the injection, %ID/g ± s, n=5)
Suppress result of experiment and show, passing through preform injection GSA, can obvious suppression when 5min
99mThe picked-up (P＜0.0001) of Tc-DMP-NGA in mouse liver in a large number do not enter liver
99mTc-DMP-NGA is trapped in the blood, also obviously increases in each internal organs picked-up such as the heart, lung, kidney.
Suppress the result of experiment explanation by preform injection GSA, can suppress
99mThe picked-up of Tc-DMP-NGA in liver.Proof
99mTc-DMP-NGA has affinity to the ASGP acceptor.
3..
99mTc-DMP-NGA is the video picture experiment in the mouse body
Get with batch 2 normal Kunming small white mouses, one in tail vein preform injection 0.1mL inhibitor (the GSA part is dissolved in physiological saline, press the dosage injection of 10mg/kg body weight), behind the 5min, with two mouse whiles in tail vein injection 0.1mL 3.7MBq
99mTc-DMP-NGA.Injection back 5,30,60,120min carry out video picture on KodakIn-Vivo Imaging System FX Pro, and with gained radioactivity image and X-ray image co-registration.The result shows
99mTc-DMP-NGA has higher liver picked-up and keeps preferably in normal mouse, and the mouse liver picked-up obviously reduces after inhibition, explanation
99mThe picked-up of Tc-DMP-NGA in liver is by the ASGP receptor mechanism.The mouse heart of 5min after inhibition partly has higher concentrating, and this is owing to not entering liver
99mTc-DMP-NGA is trapped in the blood in a large number, causes the radioactive concentration in the painstaking effort pond higher, As time goes on,
99mTc-DMP-NGA is metabolism gradually, and the picked-up of cardia also obviously reduces.
99mTc-DMP-NGA is in intravital video picture experimental result of mouse and bio distribution result and suppress experimental result always.Above-mentioned every experiment suffices to show that, technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes of the present invention has good biological property, can satisfy condition, illustrate that novel title complex of the present invention can be used as the liver cell receptor developer and applies clinically as the liver cell receptor developer.
Above-mentioned every description of test, of the present invention (
99mTc-DMP-NGA) title complex, its radiochemical purity have good biological property greater than 98%, and higher initial picked-up is arranged in liver, and have delay preferably, and along with the time increase is removed from liver; With
99mTc-GSA compares the picked-up of internal organs such as lower blood, kidney are arranged, and can satisfy the condition as the liver cell receptor developer, thereby can reduce unnecessary radiation injury, can be used as novel liver cell asialoglycoprotein receptor developer, (
99mTc-DMP-NGA) title complex has high chemical stability and good bio distribution character as a kind of novel title complex, can be used as the liver cell receptor developer and applies clinically.
Embodiment:
Below by embodiment in detail the present invention is described in detail, a kind of technetium-99 m labeled 6-hydrazino pyridine-3-formamido-novel lactose albumin complexes:
(1) preparation of DMP-NGA
Get 2,3-diacetyl propane thioic acid dicyclohexyl amine salt 0.86g places small beaker, adds the 4mL ethyl acetate, stirs the suspension liquid that obtains white, under agitation, slowly drips 10% potassium hydrogen sulfate solution, is acidified to the solution clarification, with 40mL * 3 ethyl acetate extractions.The faint yellow organic phase of gained is spent the night with anhydrous sodium sulfate drying.Behind the suction filtration, revolve to steam to remove and desolvate, obtain white solid 0.48g.Productive rate 93.8%.
In the 25mL there-necked flask, the gained white solid is dissolved in the 4mL methylene dichloride, ice bath is cooled to 0 ℃, adds the 0.25gN-N-Hydroxysuccinimide, adds the 2.1mL methylene dichloride again, is cooled to 0 ℃.Slowly drip DCC (0.44g is dissolved in the 2.1mL methylene dichloride), after dropwising, room temperature reaction 18h.Suction filtration is removed white precipitate, after mother liquor is spin-dried for, with the dissolving of a small amount of methylene dichloride, remove the trace white precipitate after, be spin-dried for solvent, clarifying yellow oil N-succinimido 2,3-diacetyl thiopropionate (SATP) 0.456g.Productive rate 61.4%.
1HNMR(CDCl3)，δ：2.41，2.45(2s，6H，CH3)，2.86(s，4H，CH2)，3.45(m，2H，CH2)，4.69(t，H，CH)。IRv/cm
-1：2932(CH3)，2854(CH2)、1816、1785、1740(C＝O)。
Get in the phosphoric acid buffer that 20mg NGA is dissolved in 1mL 0.05mol/L pH 7.5, drip the DMSO solution of the SATP of 10 μ L0.75mol/L.Room temperature reaction 2h.After reaction finishes, separating by 1 * 15cmSephadex G100 sephadex column and to remove small molecules, is leacheate with the phosphoric acid buffer of 0.05mol/L pH 7.5, obtains SATP-NGA with ultraviolet spectrophotometer at 280nm place detection collection albumen.
The hydroxylamine solution (containing the 0.5mol/L azanol, 0.025mol/L EDTA, 0.05mol/L phosphoric acid buffer) that in SATP-NGA solution, adds 0.2mL pH 7.5, the DTT aqueous solution of 40 μ L 2.27mg/mL.Room temperature reaction 2h.After reaction finishes, separating by 1 * 15cm Sephadex G100 sephadex column and to remove small molecules, is leacheate with the phosphoric acid buffer of 0.05mol/L pH 7.5, with ultraviolet spectrophotometer at 280nm place detection collection albumen.Promptly obtain part DMP-NGA.
(2)
99mThe preparation of Tc-DMP-NGA:
Its preparation process is:
A. the DMP-NGA 2mg that gets new system is dissolved in the 0.5mL phosphoric acid buffer (0.05mol/L pH6.0), adds the Seignette salt of 1mg;
B. treat that all the dissolving back adds 2mg/mL SnCl
22H
2O solution 10 μ L are in step a gained solution, and thorough mixing is even, and mixing solutions pH is 6.0;
C. with fresh
99mTcO
4 -Elutriant 0.5mL (37MBq) adds in the solution of step b preparation, fully vibration, 50 ℃ of reaction 30min.
D. after reaction finishes, carry out purifying by high performance liquid chromatography, the HPLC condition is: high performance liquid chromatograph Alltech (Model 626); Kromaisl C4 post 250 * 4.6mm, 5 μ m300
A is water (containing 0.1%TFA) mutually, and B is acetonitrile (containing 0.1%TFA) mutually; The drip washing gradient is: 0～30min:30%～70%B phase.Flow velocity 1mL/min.Each component retention time is:
99mTcO
4 -: 3.7min;
99mTc-DMP-NGA:17.4min.Collecting retention time is the peak of 17.4min, is behind the purifying
99mTc-DMP-NGA.
Behind the purifying
99MTc-DMP-NGA efficient liquid phase chromatographic analysis result shows that its retention time is 17.4min, and radiochemically pure is greater than 98%.
Claims (7)
1. technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes, the general structure of its ligand molecular dimercapto propionamido novel lactose albumin is:
In the formula: dimercapto propionamido novel lactose albumin is a part, and for connecting n galactosyl and m dimercapto propionamido simultaneously by lysine residue on the human serum albumin molecular chain, wherein n is 20-45, and m and n sum are smaller or equal to 56.
2. preparation method who prepares technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes is characterized in that:
99mThe preparation method of Tc-DMP-NGA title complex is as follows: with radiopertechnetate and dimercapto propionamido novel lactose albumin synthetic ligands; reductive agent, protectant in the presence of prepared in reaction obtain the technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes of described radioactivity, its preparation process is:
A. the DMP-NGA part being dissolved in the damping fluid, is the weight ratio of 1:0.2～10 according to protective material than part, adds protective material;
B. be that the weight ratio of 1:25～500 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-
99mDrip washing obtains in the Tc producer
99mTcO
4 -Leacheate adds in the solution of step b preparation, reacts 10～60min behind the mixing under 20 ℃～80 ℃ conditions;
D. step c gained solution is carried out purifying by high performance liquid chromatography.
3. the preparation method of technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes as claimed in claim 2, it is characterized in that: the protective material of stating described in the above-mentioned steps a is: Seignette salt, its consumption is: 0.5mg-5mg.
4. the preparation method of technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes as claimed in claim 2, it is characterized in that: the damping fluid described in the above-mentioned steps a is: 0.05mol/L pH6.0 phosphoric acid buffer, consumption are 0.1mL～5mL.
5. the preparation method of technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes as claimed in claim 2, it is characterized in that: the described reductive agent described in the above-mentioned steps b is: radiopertechnetate is reduced to
99mTc
5+Conventional chemical reagent, be preferably two hydrated stannous chlorides, former dose of consumption is: 0.01mg-0.04mg.
6. the preparation method of technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes as claimed in claim 2 is characterized in that: the dimercapto propionamido novel lactose albumin part described in the above-mentioned preparation method, and its part consumption is 1mg-5mg; Reductive agent is the weight ratio of 1:25～500 than part, and protective material is the weight ratio of 1:0.2～10 than part.
7. technetium-99 m labeled dimercapto propionamido novel lactose albumin complexes as claimed in claim 1 or 2 and preparation method thereof is characterized in that: described title complex is as the application of liver receptor developer at the field of nuclear medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670227A (en) * | 2012-06-11 | 2012-09-19 | 毛一雷 | Method for detecting liver diethylenetriamine pentaacetic acid-galactosyl-human serum albumin (GSA) uptake index |
| CN106267221A (en) * | 2015-06-04 | 2017-01-04 | 上海原子科兴药业有限公司 | A kind of technetium [99mtc] labeling method of macroaggregated albumin injection |
-
2009
- 2009-03-09 CN CNA2009100793695A patent/CN101486763A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670227A (en) * | 2012-06-11 | 2012-09-19 | 毛一雷 | Method for detecting liver diethylenetriamine pentaacetic acid-galactosyl-human serum albumin (GSA) uptake index |
| CN102670227B (en) * | 2012-06-11 | 2014-07-30 | 毛一雷 | Method for detecting liver diethylenetriamine pentaacetic acid-galactosyl-human serum albumin (GSA) uptake index |
| CN106267221A (en) * | 2015-06-04 | 2017-01-04 | 上海原子科兴药业有限公司 | A kind of technetium [99mtc] labeling method of macroaggregated albumin injection |
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Open date: 20090722 |