CN102993243B - 99mTc marked glucose derivative and preparation method and application thereof - Google Patents
99mTc marked glucose derivative and preparation method and application thereof Download PDFInfo
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- CN102993243B CN102993243B CN201210551831.9A CN201210551831A CN102993243B CN 102993243 B CN102993243 B CN 102993243B CN 201210551831 A CN201210551831 A CN 201210551831A CN 102993243 B CN102993243 B CN 102993243B
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Abstract
The invention provides a tumoraffin 99mTc marked glucosamine derivative (CBADG) and a preparation method and an application thereof. The preparation method comprises the following steps: converting amino-D-glucose into 2-(4-carboxyl-1-butylamide)-2-deoxy-D-glucose ligand (CBADG), and then marking directly with 99mTc and 99mTc(CO)3 to obtain the corresponding complex of 99mTc-CBADG and 99mTc(CO)3-CBADG. The complex of 99mTc-CBADG and 99mTc(CO)3-CBADG prepared by the invention has the advantages of high radiochemical purity, high ratio of tumor/blood and tumor/muscle, and is favorable for tumor intake and detention and the like, and the novel tumor image agent prepared by the complex is worthy to be popularized.
Description
Technical field
The present invention relates to
99mthe radiopharmaceutical chemistry of Tc mark and clinical nuclear medicine technical field, relate to specifically
99maminoglucose sugar derivatives (CBADG) of Tc mark and its preparation method and application.
Background technology
Tumour is that body is under various carcinogenic factor effect, some cells of local organization lose the normal regulation to its growth on gene level, cause its clonal abnormality hyperplasia and the true tumor formed, it is a kind of disease of serious harm human health, is also one of focus of scientific research.At present, malignant tumour has become the primary killers of harm humans health.According to Beijing Municipal Health Bureau, what Beijing's cause of the death came the first five is malignant tumour, cerebro-vascular diseases, heart trouble, respiratory system disease and Injuries and poisoning respectively, and wherein tumour causes death to account for 24.55% of total death toll.In the therapeutic process of tumour, methods for the treatment of is not most important, and the early diagnosis of tumour is only key.Research shows, early diagnosis early treatment, and the tumour patient of 50% can be cured.Radionuclide image can reflect the change of the physiology of tumour, pathology, metabolism and function, and radionuclide radionuclide imaging method is a kind of Non-invaive examination method, and plurality of advantages makes radionuclide image become the main method of diagnosing tumor.
In many tumor imaging medicaments,
18f-fluorodeoxyglucose ([
18f] FDG) be current clinical application tumor developer the most widely.In human body [
18f] FDG has the metabolic process similar to glucose, it can enter tumour cell through glucose transporter, then through hexokinase effect be converted into 6-phosphoric acid-[
18f] FDG, 6-phosphoric acid-[
18f] FDG can not metabolism further, 6-phosphoric acid simultaneously-[
18f] FDG is electronegative freely can not pass through cytolemma, is finally trapped in tumour cell.[
18f] FDG PET glucose metabolism video picture is very effective to therapeutic evaluation before and after the discriminating of the most of innocent and malignant tumour of human body, the stage and step of tumour, various treatment means etc.But [
18f] FDG is a kind of pet imaging agent, test set is expensive, and testing cost is high, simultaneously
18the transformation period of F is short, needs fast radiochemistry to synthesize, and these hinder its application in clinical diagnosis all to a certain extent.Therefore, develop that a kind of to prepare easy and cheap novel tumor developer particularly necessary.
99mtc has excellent nulcear properties, and can conveniently obtain from molybdenum PertechnetateSodium Iniection, is current most popular SPECT video picture nucleic.?
99min the research of the glucalogue of Tc mark, remove
99mtc-ethylenedicysteine-deoxyglucose (is called for short
99mtc-ECDG) entered outside clinical investigation phase, all the other are all still in the laboratory study stage.
99mtc-ECDG serum is except slow, and target/non-target ratio is lower, thus affects video picture quality.Now,
99mtc (CO)
3the research of caryogamy compound is
99mthe study hotspot of Tc radiopharmaceutical chemistry, therefore combines
99mthe new development of Tc pharmaceutical chemistry and marking method, the excellent property of further development of new
99mtc labelled glucose analog derivative (CBADG) has important practical significance as tumor developer, is also that Today radiation medicinal chemistry art needs one of important topic solved.
Summary of the invention
The object of this invention is to provide a class, to have radiochemical purity high, tumor uptake and being detained, tumour/blood and tumour/muscle ratio high, tumoraffin
99mthe aminoglucose carbohydrate derivative of Tc mark, also provides its preparation method and the application as tumor developer simultaneously.
In order to achieve the above object, the present invention is by the following technical solutions:
99mthe aminoglucose sugar derivatives of Tc mark, is amino-D-Glucose is converted into 2-(4-carboxyl-1-amide-based small)-2-deoxy-D-glucose part (CBADG), then carries out it
99mtc directly mark and
99mtc (CO)
3core mark is prepared into corresponding
99mtc-CBADG and
99mtc (CO)
3-CBADG title complex.
99mthe preparation method of the aminoglucose sugar derivatives (CBADG) of Tc mark is as follows:
A. the synthesis of part CBADG:
Appropriate amino D-Glucose hydrochloride is joined in flask, appropriate triethylamine and deionized water is added in flask, be placed in ice-water bath stirring and dissolving, then slowly dropping is dissolved with Pyroglutaric acid/acetone soln in right amount, stirring reaction 2.5h-4h, whole reaction process temperature controls at 0 DEG C-10 DEG C; Revolve and steam to obtain light brown liquid of vicidity; In this liquid, add appropriate Glacial acetic acid, room temperature leaves standstill 2h, occurs white precipitate, suction filtration, with ethanol/washed with diethylether, obtains white powder with 95% ethyl alcohol recrystallization, is part CBADG;
Its synthetic route is:
B.
99mthe preparation of Tc-CBADG:
Get penicillin bottle, add 25.0mg CBADG part, 0.24mgSnCl
2h
2o and 0.5ml physiological saline, regulates pH=8.5, then adds 37 ~ 370MBq's
99mtcO
4 -fresh leacheate, shakes up, and constant temperature 20min in 80 DEG C of water-baths, obtains described
99mtc-CBADG title complex;
C.
99mtc (CO)
3the preparation of-CBADG:
By weight (5-200): (10 ~ 400): (15-600): (20-800) weighing sodium carbonate, sodium borohydride, Rochelle salt and lactose are placed in container, add intermediate water and make dissolution of solid, after sealing, logical CO gas 10-20 minute, then adds appropriate Na
99mtcO
4(37 ~ 740MBq), boiling water bath heating 20-30 minute, cooling obtains [
99mtc (CO)
3(H
2o)
3]
+intermediate; 20mg CBADG is joined above-mentioned [
99mtc (CO)
3(H
2o)
3]
+intermediate, regulates pH to be 8-9 after mixing, reacts 20-30 minute, namely obtain described under 100 DEG C of water-baths
99mtc (CO)
3-CBADG title complex.
Chemosynthesis reagent described above is all commercial goods, is conveniently easy to get.
Synthesized by above method
99mtc-CBADG and
99mtc (CO)
3-CBADG complex preparation novel
99mtc tumor developer, its radiochemical purity is all greater than 90%.
In tumor-bearing mice body, biodistribution experiments result shows
99mtc-CBADG and
99mtc (CO)
3the delay that-CBADG title complex has high picked-up to become reconciled in tumour, the important target/non-target ratio such as tumour/blood, tumour/muscle is good, can be used as novel tumor developer.
Will
99mtc-CBADG with
99mtc (CO)
3-CBADG,
99mtc-ECDG (David J.et al Imaging with
99mtc-ECDG Targeted at the Multifunctional Glucose Transport System:Feasibility Study with Rodents [J] .Radiology, 2003,226 (2): 465-473) in tumor-bearing mice body, Biodistribution data compares, and the results are shown in Table 1.
Table 1
99mtc-CBADG,
99mtc (CO)
3-CBADG,
99mtc-ECDG after injection 4h in tumor-bearing mice body Biodistribution data compare (%ID/g)
Above result shows,
99mtc-CBADG with
99mtc (CO)
3the picked-up of-CBADG in tumour and tumour/muscle, tumour/blood ratio are all better than
99mtc-ECDG, can apply as novel tumor developer.
Experiment shows,
99mtc-CBADG with
99mtc (CO)
3the performance of-CBADG title complex is as follows:
1.
99mthe chromatography qualification of Tc-CBADG:
Thin-layer chromatography chromatogram (TLC) identify: adopt two kinds of systems to be respectively, polyamide layer as support acetonitrile as developping agent; Xinhua's filter paper is support, and physiological saline is developping agent.The tomographic results measured is in table 2.
Tomographic results (the R of each component of table 2
fvalue)
The radiochemical purity of the marker measured by above-mentioned chromatography is identified is greater than 90%.
2.
99mtc (CO)
3high pressure liquid chromatography (HPLC) qualification of-CBADG
High pressure liquid chromatography (HPLC) is identified: Waters600 type high pressure liquid chromatograph, Kromasil C18 reversed-phase column (25cm × 4.6mm × 5 μm).In table 3, flow velocity is 1.0ml/min to drip washing condition of gradient elution (A is that aqueous phase contains 0.1%TFA, and B is that acetonitrile is mutually containing 0.1%TFA), and the retention time (Rt) of each component of mensuration is respectively: [
99mtc (CO)
3(H
2o)
3]
+: 12.34min;
99mtc (CO)
3-CBADG:3.71min, the chromatographic results of gained shows what (t=3.71min has single radioactivity main peak) showed to generate
99mtc (CO)
3the radiochemical purity of-CBADG title complex is greater than 90%.
The condition of gradient elution of table 3 title complex
3. the mensuration of the lipid of title complex
Get (0.025mol/L) phosphate buffered saline buffer of 0.99mL pH7.4 in 10mL centrifuge tube, 1.0mL n-Octanol and 0.01mL complex solution is added in centrifuge tube, cover stopper, fully shake up, centrifugal 5min (4000r/min).Then from organic phase and aqueous phase, take out 0.1mL respectively, measure the radiocounting of two-phase, and calculate title complex lipid P (radioactive activity of the radioactive activity/aqueous phase of P=organic phase).Record
99mtc-CBADG and
99mtc (CO)
3the logP value of-CBADG title complex is respectively-2.50 ± 0.02 and-1.42 ± 0.25, illustrates that it is hydroaropic substance.
4. the Stability Determination of title complex
By what marked
99mtc-CBADG and
99mtc (CO)
3-CBADG title complex is at room temperature placed different time (1,2,3,4,5,6 hour) and is measured its radiochemical purity afterwards, experimental result show title complex placement after 6 hours radiochemical purity be all greater than 90%, it is described, and at room temperature vitro stability is good.
5. the biodistribution experiments of title complex in bearing mouse model
From the tail vein injection 0.10mL complex solution (about 7.4 × 10 of lotus S180 sarcoma model mouse
5bq), 0.5h, 2h, 4h sacrificed by decapitation small white mouse after injection.Get its heart, liver, lung, kidney, spleen, stomach, bone, muscle, intestines, tumour, Xue Deng related organization and organ, weigh after cleaning, and survey its radiocounting on FM-2000 type technetium analyser, the small white mouse number of each phase is 5.Calculate every gram of percentage injected dose (%ID/g) of each tissue.The results are shown in Table 4 and table 5:
Table 4
99mtc-CBADG is at lotus S180 sarcoma Biodistribution in mice (n=5) %ID/g
Table 5
99mtc (CO)
3-CBADG is at lotus S180 sarcoma Biodistribution in mice (n=5) %ID/g
Embodiment:
Below by embodiment in detail the present invention is described in detail: a class
99mthe aminoglucose sugar derivatives of Tc mark, is amino-D-Glucose is converted into 2-(4-carboxyl-1-amide-based small)-2-deoxy-D-glucose part (CBADG), then carries out it
99mtc directly mark and
99mtc (CO)
3core mark is prepared into corresponding
99mtc-CBADG and
99mtc (CO)
3-CBADG title complex.
99mthe preparation method of the aminoglucose sugar derivatives (CBADG) of Tc mark is as follows:
A. the synthesis of part CBADG:
By 1g glucosamine hydrochloride (analytical pure, AlafAesar company produces) join in 25mL round-bottomed flask, add 2mL deionized water dissolving, add 0.68mL triethylamine again, gained solution ice-water bath cools, and under agitation adds acetone/Pyroglutaric acid (analytical pure, the Beijing Chemical Plant produces) solution of 5mL 0.116g/mL, stir 4h, whole reaction process temperature controls at 0 DEG C ~ less than 10 DEG C.Concentrated by rotary evaporation at 40 DEG C, adds the Glacial acetic acid of residuum 4 times of volumes, and room temperature is placed 2h and obtained white precipitate, suction filtration, obtains white powder, obtain white product be CBADG with 95% ethyl alcohol recrystallization with ethanol/washed with diethylether.The data of its infrared spectra are: v (IR)/cm
-1: 3365,2916,1539 (N-H); 3383 (O-H); 1691,1646 (C=O); 1020 (C-O-C).
Nuclear-magnetism
1hNMR (D
2o), δ is: 4.93 (d, J=3.5Hz, isomerH), 4.43 (d, J=8.4Hz, isomerH), 3.65 ~ 3.17 (m, 6H), 2.17 ~ 2.06 (m, 4H), 1.67 ~ 1.60 (m, 2H).
MS(ESI)：m/z 292，[M-H]
-。
B.
99mthe preparation of Tc-CBADG
By 25mg CBADG part, 0.24mgSnCl
2be dissolved in 1mL physiological saline, regulate pH to be 8.5, add 37 ~ 370MBq's
99mtcO
4 -leacheate 0.5-1mL, 80 DEG C of reaction 20-30min, namely obtain described
99mtc-CBADG title complex.
C.
99mtc (CO)
3the preparation of-CBADG:
By weight (5-200): (10-400): (15-600): (20-800) weighing sodium carbonate, sodium borohydride, Rochelle salt and lactose are placed in container, add intermediate water and make dissolution of solid, after sealing, logical CO gas 10-20 minute, then adds appropriate Na
99mtcO
4(37 ~ 740MBq), boiling water bath heating 20-30 minute, cooling obtains [
99mtc (CO)
3(H
2o)
3]
+intermediate; 20mg CBADG is joined above-mentioned [
99mtc (CO)
3(H
2o)
3]
+intermediate, regulates pH to be 8-9 after mixing, reacts 20-30 minute, namely obtain described under 100 DEG C of water-baths
99mtc (CO)
3-CBADG title complex.
Claims (3)
1. a class
99mthe aminoglucose sugar derivatives of Tc mark, is characterized in that: be amino-D-Glucose is converted into 2-(4-carboxyl-1-amide-based small)-2-deoxy-D-glucose part (CBADG), then carry out it
99mtc directly marks and is prepared into accordingly
99mtc-CBADG title complex.
2. preparation is as claimed in claim 1
99mtc-CBADG title complex method, comprises the following steps:
A. the synthesis of part CBADG:
Appropriate amino D-Glucose hydrochloride is joined in flask, appropriate triethylamine and deionized water is added in flask, be placed in ice-water bath stirring and dissolving, then slowly dropping is dissolved with the acetone soln of Pyroglutaric acid in right amount, stirring reaction 2.5h-4h, whole reaction process temperature controls at 0 DEG C-10 DEG C; Revolve and steam to obtain light brown liquid of vicidity; In this liquid, add appropriate Glacial acetic acid, room temperature leaves standstill 2h, occurs white precipitate, suction filtration, with ethanol/washed with diethylether, obtains white powder with 95% ethyl alcohol recrystallization, is part CBADG;
B.
99mthe preparation of Tc-CBADG:
Get penicillin bottle, add 25.0mg CBADG part, 0.24mgSnCl
2h
2o and 0.5ml physiological saline, regulates pH=8.5, then adds 37 ~ 370MBq's
99mtcO
4-fresh leacheate, shakes up, and constant temperature 20min in 80 DEG C of water-baths, obtains described
99mtc-CBADG title complex.
3. as claimed in claim 1
99mtc-CBADG title complex prepares the application in tumor developer in nuclear medicine image field.
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| CN107245087B (en) | 2017-06-15 | 2019-08-23 | 北京师宏药物研制中心 | 99mTc marks glucosan derivative and preparation method and application containing isonitrile |
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| CN101337081A (en) * | 2008-08-22 | 2009-01-07 | 北京师范大学 | Medicine box for preparing 99mTc complex and preparation method and use thereof |
| CN102146098B (en) * | 2011-03-02 | 2013-08-07 | 北京师范大学 | Preparation method and application of 99mTc labeled D-glucose coordination compound |
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Non-Patent Citations (1)
| Title |
|---|
| Imaging with 99mTc ECDG Targeted at the Multifunctional GlucoseTransport System: Feasibility Study with Rodents;David J. Yang et al.;《Radiology》;20031231;第226卷(第2期);第465-473页 * |
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