CN102977149B - A kind of 99mtcO (MNXT) 2title complex and its preparation method and application - Google Patents
A kind of 99mtcO (MNXT) 2title complex and its preparation method and application Download PDFInfo
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- CN102977149B CN102977149B CN201210551884.0A CN201210551884A CN102977149B CN 102977149 B CN102977149 B CN 102977149B CN 201210551884 A CN201210551884 A CN 201210551884A CN 102977149 B CN102977149 B CN 102977149B
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Abstract
The invention discloses one
99mtcO (MNXT)
2title complex and preparation method and application, this title complex with
99mcore centered by TcO core, two MNXT ligand moleculars, 4 sulphur atoms with
99mtc coordination obtains
99mtcO (MNXT)
2title complex.Ligand exchange method is adopted to prepare
99mtcO (MNXT)
2title complex, good hydrophilic property, have certain weary oxygen selective, tumor uptake is high, and tumour/muscle, tumour/blood ratio is good, can prepare the novel tumor anoxia developing agent becoming a kind of excellent property.
Description
Technical field
The present invention relates to radiopharmaceutical chemistry and clinical nuclear medicine technical field, relate to one specifically
99mtcO (MNXT)
2title complex and its preparation method and application.
Background technology
Tissue anoxia is the principal character of many important diseases clinically, ubiquity tissue anoxia phenomenon in human and animal's tumour.Due to the existence of weary oxygen, the tolerance that tumour is produced for radiation and chemotherapy causes tumour to be difficult to cure and easily recurrence.The oxygen level of Tumor Patient Before and After Treatment tumour is detected, for detection malignant tumour and metastasis to judge that result for the treatment of tool is of great significance.The method of current inspection tumor hypoxia has a variety of, and wherein nuclear medicine radionuclide image technology is one of them.Sub-connection is divided by radionuclide and radioactivity sensitizer, form the tumor hypoxia imaging medicament with anoxic cell specific binding, and tumor hypoxia degree can be evaluated non-invasively in live body level by nuclear medicine image (SPECT, PET), the cancer immunotherapies suitable for selection of clinical provides foundation.
99mthe nitro glyoxaline tumor hypoxia developer of Tc mark is the focus of international radiopharmaceutical chemistry research for many years always.Due to
99mtcN triple bond has very high chemical stability and special bio distribution character, bibliographical information one
99mtcN core mark metronidazole xanthogenate title complex (
99mtcN (MNXT)
2) as potential tumor hypoxia developer (MadhabaB.Mallia, MeeraVenkatesh, eta1.Anovel [
99mtcN]
2+complexofmetronidazolexanthateasapotentialagentfortarget inghypoxia..Bioorganic & MedicinalChemistryLetters, 2005,15:3398-3401), but its tumor uptake value is on the low side and liver uptake values is higher, is therefore still necessary to develop more preferably novel tumor anoxia developing agent.
99mtc-gluceptate (
99mtc-GH) be with [
99mtcO]
3+centered by the title complex of core, structure is determined, and its easily and the generation of other part generation ligand exchange reactions new [
99mtcO]
3+caryogamy compound, so use
99mtc-GH as [
99mtcO]
3+the labelled precursor of caryogamy compound prepare novel [
99mtcO]
3+caryogamy compound becomes the new way seeking Novel radioactive medicine.
99mthe preparation successful medicine box of Tc-GH, this be [
99mtcO]
3+radiopharmaceutic the applying of core mark lays a solid foundation.Therefore prepare [
99mtcO]
3+core metronidazole xanthogenate title complex, is called for short
99mtcO (MNXT)
2title complex is used for the novel tumor anoxia developing agent that clinical expansion uses, and is the important topic that Today radiation medicinal chemistry art needs to solve.
Summary of the invention
Object of the present invention provides that a kind of radiochemical purity is high, good stability, prepare easy and cheap, is applied in tumor hypoxia imaging art
99mtcO (MNXT)
2title complex; Also provide its preparation method simultaneously.
In order to achieve the above object, the present invention by the following technical solutions: a kind of
99mtcO (MNXT)
2title complex, its structural formula is:
In this structural formula: with [
99mtcO]
3+core centered by core, in two MNXT ligand moleculars 4 sulphur atoms with
99mtc coordination obtains
99mtcO (MNXT)
2title complex.
99mtcO (MNXT)
2the preparation method of title complex is as follows: adopt ligand exchange method preparation
99mtcO (MNXT)
2, in GH froze-dried kit, add appropriate Na
99mtcO
4, shake up after rear room temperature places 15 minutes and namely obtain
99mtc-GH.Be 9 ~ 10 by 0.1mol/LNaOH regulator solution pH value, joined by 1 ~ 2mgMNXT in above-mentioned solution, after mixing, boiling water bath heats 30 minutes, namely obtains
99mtcO (MNXT)
2title complex.GH wherein in GH froze-dried kit represents gluceptate, and its molecular formula is CH
2oH (CHOH)
5cOOH.
Above-mentioned chemical reagent used is all commercial goods, and wide material sources, easily obtain; Wherein MNXT according to document (MadhabaB.Mallia, MeeraVenkatesh, etal.Anovel [
99mtcN]
2+complexofmetronidazolexanthateasapotentialagentfortarget inghypoxia..Bioorganic & MedicinalChemistryLetters, 2005,15:3398-3401) synthesize voluntarily.
Prepared by aforesaid method
99mtcO (MNXT)
2under title complex room temperature, vitro stability is good, and its radiochemical purity is greater than 90%.Will
99mtcO (MNXT)
2with
99mtcN (MNXT)
2in tumor-bearing mice body, Biodistribution data compares, and the results are shown in Table 1.
Table 1
99mtcO (MNXT)
2with
99mtcN (MNXT)
2after injection 30min, in tumor-bearing mice body, Biodistribution data compares (%ID/g)
With
99mtcN (MNXT)
2compare,
99mtcO (MNXT)
2title complex has higher tumor uptake and tumour/blood and tumour/muscle ratio, can apply as a kind of novel tumor anoxia developing agent.
Experiment shows,
99mtcO (MNXT)
2the performance of title complex is as follows:
1.
99mtcO (MNXT)
2thin-layer chromatography (TLC) qualification
Thin-layer chromatography chromatogram (TLC) is identified: with polyamide layer as support, with physiological saline as developping agent, the tomographic results of mensuration 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.
99mtcO (MNXT)
2the mensuration of the lipid of title complex
The phosphate buffered saline buffer (0.025mol/L) getting 1.0mLpH7.4, in 10mL centrifuge tube, adds 1.0mL n-Octanol and 0.01mL in centrifuge tube
99mtcO (MNXT)
2solution, covers stopper, fully shakes up, centrifugal 5min (5000r/min).Then from organic phase and aqueous phase, take out 0.1mL respectively, measure the radiocounting of two-phase, and calculate its partition ratio P (radioactive activity of the radioactive activity/aqueous phase of P=organic phase), record logP=-1.47, explanation
99mtcO (MNXT)
2it is a kind of water-soluble substances.
3.
99mtcO (MNXT)
2the Stability Determination of title complex
By what marked
99mtcO (MNXT)
2title complex measures its radiochemical purity after at room temperature placing 6 hours, and experimental result shows
99mtcO (MNXT)
2title complex placement after 6 hours radiochemical purity be greater than 90%, explanation
99mtcO (MNXT)
2title complex at room temperature vitro stability is good.
4.
99mtcO (MNXT)
2the cell in vitro picked-up experiment of title complex
S180 cell is joined in the DMEM nutrient solution containing 10% foetal calf serum.Taking out 20mL concentration is respectively 2.0 × 10
6the above-mentioned S180 cell suspension of individual cells/ml, is transferred in 2 reaction flasks, is filled with respectively through water saturated containing 95%N
2and 5%CO
2(weary oxygen), and containing 95% air and 5%CO
2the mixed gas of (normally containing oxygen), whole system constant temperature is in 37 DEG C of water-baths.Passing into containing 95%N in cell suspending liquid
2and 5%CO
2after mixed gas 30-45min, make the concentration of oxygen in solution be brought down below 10ppm, cause the weary oxygen of system.Under two states, by 0.2mL
99mtcO (MNXT)
2title complex joins in cell suspending liquid, makes the radioactive activity of marker in final cell suspension liquid reach 0.2MBq/mL, and mass concentration reaches about 0.7 μ g/mL.1.1-1.2mL Cell suspension samples is got respectively when 15,30,60,120,180 and 240min, each sample parallel gets 5 200 μ L in centrifuge tube, the centrifugal 5min of 1500r/min is with isolated cell and nutrient solution, get 180 μ L supernatant liquors, measure radiocounting with well type γ scintillation probe together with 20 remaining μ L respectively containing the solution of S180 cell.The picked-up per-cent of cell is: Uptake%=[C20 μ L-C180 μ L/9]/[C20 μ L+C180 μ L] × 100%, the results are shown in Table 3.
Table 3
99mtcO (MNXT)
2the cell in vitro picked-up experiment of title complex
Cell in vitro picked-up experiment shows, after 30min
99mtcO (MNXT)
2the uptake values of title complex in anoxic cell all higher than its uptake values in aerobic cell, shows that it has certain weary oxygen selective.
5.
99mtcO (MNXT)
2the biodistribution experiments of title complex in bearing mouse model
From the tail vein injection 0.10mL of lotus S180 sarcoma model mouse
99mtcO (MNXT)
2complex solution (about 7.4 × 10
5bq), 0.5h, 2h, 4h sacrificed by decapitation small white mouse after injection.Get related organization and the organs such as its heart, liver, lung, kidney, spleen, bone, brain, muscle, blood, tumour, weigh after cleaning, and on FM-2000 type technetium analyser, survey its radiocounting, time each, the small white mouse number of item is 5.Calculate every gram of percentage injected dose (%ID/g) of each tissue.The results are shown in Table 4.
Table 4
99mtcO (MNXT)
2the bio distribution of title complex in bearing mouse model (x ± s, n=5, %ID/g)
Embodiment:
Below by embodiment in detail the present invention is described in detail: a kind of
99mtcO (MNXT)
2title complex, its structural formula is:
In this structural formula: with [
99mtcO]
3+core centered by core, in two MNXT ligand moleculars 4 sulphur atoms with
99mtc coordination obtains
99mtcO (MNXT)
2title complex.
99mtcO (MNXT)
2the preparation method of title complex is as follows:
Preparation GH froze-dried kit: by by GH, SnCl
2.2H
2o is dissolved in appropriate intermediate water by the weight ratio of 200: 1, is sub-packed in clean penicillin bottle, through freeze-dried back, then by 74MBq's after fully dissolving
99mtcO
4 -leacheate 1-2mL joins in GH froze-dried kit, shakes up, and under room temperature (20-30 DEG C), reaction obtains for 15 minutes
99mtc-GH solution; Regulate with 0.1mol/LNaOH
99mtc-GH solution ph is 9 ~ 10, is that the MNXT aqueous solution of 1g/L joins above-mentioned by 1mL concentration
99min Tc-GH solution, react 30 minutes in boiling water bath after mixing, namely obtain described
99mtcO (MNXT)
2title complex.
Claims (3)
1. one kind
99mtcO (MNXT)
2title complex, is characterized in that: the structural formula of title complex is:
In this structural formula: with
99mcore centered by TcO core, 4 sulphur atoms of two MNXT ligand moleculars with
99mtc coordination obtains
99mtcO (MNXT)
2title complex.
2. preparation is a kind of as claimed in claim 1
99mtcO (MNXT)
2the preparation method of title complex, its processing step is: adopt ligand exchange method preparation
99mtcO (MNXT) 2, adds the Na of 37 ~ 740MBq in GH froze-dried kit
99mtcO
4-leacheate 1-5mL, shakes up after rear room temperature places 15 minutes and obtains
99mtc-GH; Be 9 ~ 10 by 0.1mol/LNaOH regulator solution pH value, joined by 1 ~ 2mgMNXT in above-mentioned solution, after mixing, boiling water bath heats 30 minutes, obtains of the present invention
99mtcO (MNXT)
2title complex.
3. as claimed in claim 1
99mtcO (MNXT)
2title complex in radiopharmaceutical chemistry field for the preparation of the application in tumor hypoxia developer.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101486707A (en) * | 2009-02-27 | 2009-07-22 | 北京师范大学 | 2-methyl-5-nitro glyoxaline compound, preparation and use thereof |
| CN101555229A (en) * | 2009-05-21 | 2009-10-14 | 北京师范大学 | Nitro imidazole xanthogenate complex marked by <99>Tc<m>O, preparation method and applications |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101486707A (en) * | 2009-02-27 | 2009-07-22 | 北京师范大学 | 2-methyl-5-nitro glyoxaline compound, preparation and use thereof |
| CN101555229A (en) * | 2009-05-21 | 2009-10-14 | 北京师范大学 | Nitro imidazole xanthogenate complex marked by <99>Tc<m>O, preparation method and applications |
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Granted publication date: 20151125 Termination date: 20161219 |