CN101555263B - D-glucose dithiocarbamate complex marked by <99m>TcO, preparation method and applications thereof - Google Patents
D-glucose dithiocarbamate complex marked by <99m>TcO, preparation method and applications thereof Download PDFInfo
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Abstract
The invention discloses a D-glucose dithiocarbamate complex labeled by <99m>TcO nucleus, a preparation method and applications thereof; the formula of the complex is <99m>TcO(DGDTC)2, <99m>Tc(V)O<3+> is taken as a central nucleus and the complex has a geometric configuration with the shape of an irregular square pyramid, wherein O atom in Tc=O bond is positioned at the top point and four sulphur atoms provided by two DGDTC ligand molecules are positioned at the four points of the bottom surface. By the technical steps of synthesis of ligand DGDTC and preparation of <99>Tc<m>O (DGDTC)2 complex, the <99>Tc<m>O (DGDTC)2 complex is obtained. The D-glucose dithiocarbamate complex has high radiochemical purity and good stability, has higher uptake value and good detention in tumor and higher ratio of tumor/muscle, and is suitable for being promoted and applied as a novel tumor imaging agent.
Description
Affiliated technical field
The present invention relates to
99mThe radiopharmaceutical chemistry and the clinical nuclear medicine technical field of TcO nuclear mark relate to a kind of specifically
99mTcO nuclear mark D-glucose dithiocarbamate complexes and its production and application.
Background technology
Now, malignant tumour has become the main killer of harm humans health.Preventing and treating in the process of tumour, methods of treatment is not most important, and the early diagnosis of tumour is only key.Studies show that, the early diagnosis early treatment, 50% tumour patient can be cured.Radionuclide image can reflect the variation of physiology, pathology, metabolism and the function of tumour, and radionuclide radionuclide imaging method is a kind of non-invasive detection method, and plurality of advantages makes radionuclide image become the main method of diagnosing tumor.In many tumor imaging medicaments,
18The F-fluorodeoxyglucose ([
18F] FDG) be present clinical application tumor developer the most widely, enjoy the good reputation of " battle steed ".But [
18F] FDG is a kind of pet imaging agent, the test set costliness, the testing cost height, simultaneously
18The transformation period of F is short, needs fast radiochemistry synthetic, and these have hindered its widespread use in clinical to a certain extent.Therefore, development is a kind of prepares easy and cheap novel tumor developer and is necessary especially.
99mTc has good nulcear properties, and the transformation period is 6.02h, the gamma-rays of emission 140keV, and cheap and easy to get, be present most popular SPECT video picture nucleic.And find under study for action,
99mThough Tc labelled glucose derivative has higher picked-up in tumour, its serum removes slower, and is higher at the bottom of the principal, thereby influence the video picture quality.Therefore further development is novel makes things convenient for clinical application
99mTc labelled glucose class tumor developer has important practical significance.With amino-D-conversion of glucose be D-glucose dithiocarbamate part (D-glucose dithiocarbamate, be called for short: DGDTC), then by with
99mTc-GH (GH: gluceptate CH
2OH (CHOH)
5COOH) ligand exchange reaction takes place, preparation is corresponding
99mTcO (DGDTC)
2Title complex comes as the novel tumor developer, is the important topic that current present technique field need solve.
Summary of the invention
Purpose of the present invention provides a kind of radiochemical purity height, good stability, prepares easyly and cheap, is applied in the tumor imaging field
99mTcO nuclear mark D-glucose dithiocarbamate complexes also provides simultaneously
99mThe preparation method of TcO nuclear mark D-glucose dithiocarbamate complexes.
In order to achieve the above object, the present invention by the following technical solutions: a kind of
99mTcO nuclear mark D-glucose dithiocarbamate complexes, its general formula is
99mTcO (DGDTC)
2, its structural formula is:
This title complex with [
99mTc (V) O]
3+Be centronucleus, have a PYR geometric configuration of irregular pros, wherein the O atom in the Tc=O key is positioned at vertex position, and four sulphur atoms that two DGDTC ligand moleculars provide are positioned at four points of bottom surface.
99mTcO (DGDTC)
2The preparation method of title complex is as follows:
A. part DGDTC's is synthetic:
A certain amount of glucosamine hydrochloride is added in the reaction vessel, in reaction vessel, add the NaOH aqueous solution, slowly drip CS then
2, stirring 2h-3h, the entire reaction course temperature will be controlled at below 10 ℃.Steaming desolventizes then, the residuum recrystallizing methanol, and getting yellow powder is part DGDTC.
Its synthetic route is:
B.
99mTcO (DGDTC)
2Preparation:
With 37～370MBq's
99mTcO
4 -Leacheate 1-5mL joins in the GH froze-dried kit, fully shakes up, and after solid dissolved fully, room temperature (20～30 ℃) reaction down obtained in 15～30 minutes
99mThe TcO-GH midbody solution.With 1mL concentration is that the DGDTC aqueous solution of 5g/L joins above-mentioned
99mIn the TcO-GH midbody solution, in boiling water bath, placed 30 minutes behind the mixing, promptly obtain
99mTcO (DGDTC)
2Title complex.
99mTcO (DGDTC)
2Preparation adopt ligand exchange reaction, its reaction scheme is as follows:
99mTcO
4 -+SnCl
2·2H
2O+GH→
99mTcO-GH
99mTcO-GH+DGDTC→
99mTcO(DGDTC)
2
Above-mentioned described chemosynthesis reagent all is commercial goods, and wide material sources obtain easily.
Above-mentioned described
99mTcO (DGDTC)
2Be a kind of novel
99mThe Tc tumor developer, it with [
99mTc (V) O]
3+Nuclear is centronucleus, the radiochemical purity height, and good stability is by the aforesaid method synthetic
99mTcO (DGDTC)
2, its radiochemical purity is greater than 90%.
The bio distribution experimental result shows in the tumor-bearing mice body
99mTcO (DGDTC)
2Title complex has higher picked-up and is detained preferably in tumour, the ratio of target/non-target organ that tumour/blood, tumour/muscle etc. are important is also better, can become a kind of novel tumor developer.
Will
99mTcO (DGDTC)
2With
99mTcN (DGDTC)
2(Zhang JB.et al.Synthesis andbiological evaluation of a novel 99mTc nitrido radiopharmaceutical withdeoxyglucose dithiocarbamate, showing tumor uptake[J] .Bioorganic ﹠amp; MedicinalChemistry Letters, 2009,19 (10), 2752-2754),
99mTc-ECDG and [
18F] FDG (David J.etal Imaging with
99mTc-ECDG Targeted at the Multifunctional Glucose TransportSystem:Feasibility Study with Rodents[J] .Radiology, 2003,226 (2): 465-473) the bio distribution data relatively the results are shown in Table 1 in the tumor-bearing mice body.
Table 1
99mTcO (DGDTC)
2,
99mTcN (DGDTC)
2,
99mTc-ECDG, [
18F] FDG bio distribution data comparisons (%ID/g) in the tumor-bearing mice body behind injection 4h
Above result shows,
99mTcO (DGDTC)
2Picked-up in tumour and tumour/muscle, tumour/blood ratio all will be higher than
99mTc-ECDG.With [
18F] FDG and
99mTcN (DGDTC)
2Compare, though
99mTcO (DGDTC)
2Tumour/blood ratio is on the low side, but it has higher tumor uptake and tumour/muscle ratio, is worthy of popularization as the novel tumor developer.
Experiment shows,
99mTcO (DGDTC)
2The performance of title complex is as follows:
1.
99mTcO (DGDTC)
2Chromatography identify:
Thin-layer chromatography chromatogram (TLC) is identified: as support, as developping agent, the tomographic results of mensuration sees Table 2 with physiological saline with polyamide layer.
Tomographic results (the R of each component of table 2
fValue)
Identify that by above-mentioned chromatography the radiochemical purity of measured marker is greater than 90%.
High performance liquid chromatography (HPLC) is identified: Shimadzu SCL-10AVP type high pressure liquid chromatograph, (25cm * 4.6mm), Packard liquid dodges analyser to Kromasil 100-5C18 reversed-phase column.Moving phase is the methyl alcohol of 70% (volume fraction), sample size 5 μ L, and flow is 1mL/min, the retention time of each component of mensuration (Rt) is respectively:
99mTcO
4 -: 3.4min;
99mTcO-GH:2.1min;
99mTcO (DGDTC)
2: 2.9min, the chromatogram result of gained (t=2.9min has a radioactivity main peak) show,
99mTcO (DGDTC)
2The radiochemical purity of title complex is greater than 90%.
2.
99mTcO (DGDTC)
2The mensuration of the lipid of title complex
(0.025mol/L) phosphate buffered saline buffer of getting 0.99mLpH7.4 adds 1.0mL n-Octanol and 0.01mL in centrifuge tube in the 10mL centrifuge tube
99mTcO (DGDTC)
2Complex solution covers stopper, fully shakes up, centrifugal 5min (4000r/min).Take out 0.1mL from organic phase and aqueous phase respectively then, measure the radiocounting of two-phase, and calculate its lipid P=0.19 (radioactive activity of the radioactive activity/water of P=organic phase), record logP=-0.71, explanation
99mTcO (DGDTC)
2It is a hydroaropic substance.
3.
99mTcO (DGDTC)
2The stability of title complex is measured
Mark is good
99mTcO (DGDTC)
2Title complex is at room temperature placed different time (1,2,3,4,5,6 hour) back and is measured its radiochemical purity, and experimental result shows
99mTcO (DGDTC)
2Title complex after placing 6 hours radiochemical purity greater than 90%, explanation
99mTcO (DGDTC)
2Title complex at room temperature vitro stability is good, is suitable for the needs of clinical application.
4.
99mTcO (DGDTC)
2The bio distribution experiment of title complex in bearing mouse model:
Tail vein injection 0.10mL from lotus S180 sarcoma model mice
99mTcO (DGDTC)
2Complex solution (about 7.4 * 10
5Bq), injection back 0.5h, 2h, 4h sacrificed by decapitation small white mouse.Get related organization and organs such as its blood, the heart, liver, lung, kidney, brain, tumour, muscle, bone, weigh after cleaning, and on FM-2000 type technetium analyser, survey its radiocounting, each the time item the small white mouse number be 5.Calculate every gram percentage injected dose (%ID/g) of each tissue.The results are shown in Table 3.
Table 3
99mTcO (DGDTC)
2Bio distribution (n=5) %ID/g in lotus S180 sarcoma mouse body
5.
99mTcO (DGDTC)
2Title complex is tested in the intravital SPECT video picture of bearing mouse model:
Tail vein injection 0.10mL from lotus S180 sarcoma model mice
99mTcO (DGDTC)
2Complex solution (about 11.1MBq), behind the 4h, the anesthesia of abdominal injection Sodital.Mouse is prostrate fixing, carry out static planar imaging and use HAWKEYE VG8 type SPECT.Imaging array is 128 * 128, magnification 3.0, every frame, acquisition time 300 seconds.Adopt region of interest (region of interest, the ROI) radiocounting at technical measurement focus and the normal position of offside, the picked-up ratio of calculating tumour and healthy tissues simultaneously.The SPECT video picture is the result show
99mTcO (DGDTC)
2Have obviously in the tumour kitchen range and concentrate, the picked-up ratio of tumour and healthy tissues (T/N value) is 2.0.
Embodiment
Embodiment
Below by embodiment in detail the present invention is described in detail: a kind of
99mTcO (DGDTC)
2Title complex:
A. part DGDTC's is synthetic:
With 0.01mol glucosamine hydrochloride (analytical pure, Alaf Aesar company produces) join in the 50mL there-necked flask, add the 5mL deionized water dissolving, gained solution cools off with ice-water bath, NaOH (the analytical pure that under agitation adds 4mL 5mol/L, the Beijing Chemical Plant produces) aqueous solution, slowly drip 0.01molCS then
2(analytical pure, Shantou Xilong Chemical Factory, Guangdong) stirs 2h～3h, and the entire reaction course temperature is controlled at below 10 ℃.Steaming desolventizes, and the residuum recrystallizing methanol gets yellow powder and is DGDTC.The data of its infrared spectra are: v (IR)/cm
-1: 3427 (OH), 2925 (CH
2), 1631 (C-N), 1038 (C=S).
The theoretical value ω of each element massfraction (%) is: C 27.63, H 4.93, N 4.61, experimental value ω (%) is: C 28.00, H 5.20, N 4.85.
MS(ESI)：m/z?254，[M-23]
+·。
B.
99mTcO (DGDTC)
2Preparation
Preparation GH froze-dried kit: by with GH, SnCl
2.2H
2O is dissolved in an amount of secondary water by 200: 1 weight ratio, fully is sub-packed in the clean penicillin bottle, through freeze-dried back after the dissolving.
With 37～370MBq's
99mTcO
4 -Leacheate 1-5mL joins in the GH froze-dried kit, fully shakes up, and after solid dissolved fully, room temperature (20～30 ℃) reaction down obtained in 15～30 minutes
99mThe TcO-GH midbody solution.With 1mL concentration is that the DGDTC aqueous solution of 5g/L joins above-mentioned
99mIn the TcO-GH midbody solution, in boiling water bath, reacted 30 minutes behind the mixing, promptly obtain
99mTcO (DGDTC)
2Title complex.
Claims (3)
1. one kind
99mTcO nuclear mark D-glucose dithiocarbamate complexes, it is characterized in that: general formula is
99mTcO (DGDTC)
2, its structural formula is as follows:
This title complex with [
99mTc (V) O]
3+Be centronucleus, have a PYR geometric configuration of irregular pros, wherein the O atom in the Tc=O key is positioned at vertex position, and four sulphur atoms that two DGDTC ligand moleculars provide are positioned at four points of bottom surface.
2. preparation according to claim 1
99mThe preparation method of TcO nuclear mark D-glucose dithiocarbamate complexes, its processing step is as follows:
A. part DGDTC's is synthetic:
A certain amount of glucosamine hydrochloride is added in the reaction vessel, in reaction vessel, add the NaOH aqueous solution, slowly drip CS then
2, stirring 2h-3h, the entire reaction course temperature will be controlled at below 10 ℃, steams then to desolventize, the residuum recrystallizing methanol, getting yellow powder is part DGDTC;
Its synthetic route is:
B.
99mTcO (DGDTC)
2Preparation:
With 37～370MBq's
99mTcO
4-leacheate 1-5mL joins in the GH froze-dried kit, fully shakes up, and after solid dissolved fully, room temperature (20～30 ℃) reaction down obtained in 15～30 minutes
99mThe TcO-GH midbody solution is that the DGDTC aqueous solution of 5g/L joins above-mentioned with 1mL concentration
99mIn the TcO-GH midbody solution, in boiling water bath, placed 30 minutes behind the mixing, promptly obtain
99mTcO (DGDTC)
2Title complex;
99mTcO (DGDTC)
2Preparation adopt ligand exchange reaction, its reaction scheme is:
99mTcO
4 -+SnCl
2·2H
2O+GH→
99mTcO-GH
99mTcO-GH+DGDTC→
99mTcO(DGDTC)
2。
3. as claimed in claim 1
99mTcO nuclear mark D-glucose dithiocarbamate complexes is used to prepare tumor developer in the field of nuclear medicine.
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|---|---|---|---|
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| CN102977174B (en) * | 2012-12-19 | 2015-04-22 | 北京师范大学 | 99mTc(CO)3 nuclear-labeled macrocyclic polyamine triazole ring glucose-based complex as well as preparation and application of complex |
| CN106008636B (en) * | 2016-06-23 | 2018-03-09 | 北京师范大学 | Tc 99m labelled glucose dithiocarbamate complexes and preparation method and application |
| CN112175025B (en) * | 2020-10-13 | 2021-12-21 | 北京师范大学 | Glucose derivative containing benzene ring and application thereof |
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Address after: 100875 School of chemistry, Beijing Normal University, 19 Xinjie street, Haidian District, Beijing Patentee after: BEIJING NORMAL University Patentee after: Beijing Shihong Pharmaceutical Co., Ltd Address before: 100875 School of chemistry, Beijing Normal University, 19 Xinjie street, Haidian District, Beijing Patentee before: BEIJING NORMAL University Patentee before: Beijing Shihong drug development center |
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