CN104491889B - Application of radiolabelled monoanthracene nucleus anthraquinone compound in preparation of medicine used for detecting myocardial viability - Google Patents
Application of radiolabelled monoanthracene nucleus anthraquinone compound in preparation of medicine used for detecting myocardial viability Download PDFInfo
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- CN104491889B CN104491889B CN201410745394.3A CN201410745394A CN104491889B CN 104491889 B CN104491889 B CN 104491889B CN 201410745394 A CN201410745394 A CN 201410745394A CN 104491889 B CN104491889 B CN 104491889B
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Abstract
The invention relates to the field of medicines, in particular relates to the application field of monoanthracene nucleus anthraquinone compounds and in particular relates to application of a radiolabelled monoanthracene nucleus anthraquinone compound in preparation of a medicine used for detecting myocardial viability. The radiolabelled monoanthracene nucleus anthraquinone compound has a specific binding force on myocardial necrotic cells, and a radiation source produced by a radioactive isotope is combined with a detector, thus the aim of effectively detecting the myocardial necrotic cells is achieved.
Description
Technical field
The present invention relates to drug field, the application field of more particularly to single anthracene core anthraquinone analog compound, more specifically
Say it is to be related to single anthracene core anthraquinone analog compound of labelled with radioisotope answering in preparing for myocardial activity detection medicine
With.
Background technology
Myocardial infarction is the incidence of disease in angiocardiopathy, death rate disease higher.After myocardial infarction in infarcted region
Cell meeting degeneration necrosis, form slough, non-renewable.The area of slough is that the most important of acute myocardial infarction AMI is examined
Severed finger mark.The infarcted region of acute myocardial infarction AMI probably has 40% survival myocardium, may recover after blood flow reconstruction or
Spontaneous recovery myocardial viability.Whether the accurately reversible selection to therapeutic scheme of identification myocardial infarction patient ischemic myocardium has certainly
Qualitatively act on.Stunning myocardium, hibernating myocardium and necrotic myocardium are may be simultaneously present on the heart of miocardial infarction, the above two belong to
In survival myocardium.If patient has formd the irreversible myocardial infarction of large area and survival myocardium is little, should select
Therapeutic scheme be heart transplant or symptomatic treatment without reconstructive vascular operation treatment should be received.Therefore myocardial infarction is accurate
Diagnosis, has decisive meaning for cardiopathic treatment.
Now it is used clinically for detecting that the method for survival myocardium mainly has magnetic resonance imaging (MRI), positron emission fault
Scanning (PET) and single-photon emission tomography (SPECT), nuclear imaging, by detecting the contractile function of cardiac muscle cell, cell is new
Old metabolism evaluates myocardial viability situation with myocardial fibrosis.But because all there is limitation in every kind of method, therefore can not be accurate
Really judge the state of heart cell, cause the mistake for the treatment of method to use, delay treatment.
The content of the invention
The present invention discloses the list of labelled with radioisotope for the limitation of current myocardial cell activity detection method
Anthracene core anthraquinone analog compound is being prepared for the application in myocardial activity detection medicine.
Particularly, single anthracene core anthraquinone analog compound of labelled with radioisotope is being prepared for the aobvious of myocardial activity detection
Application in shadow agent.
Furthermore, labelled with radioisotope is that single anthracene core anthraquinone analog compound is being prepared for myocardial infarction
Application in class myocardial activity detection developer.
Further, the radio isotope be iodo- 123, iodo- 124, iodine-125, iodine -131, technetium -99, Value linear,
Ytterbium -111 or ytterbium -113.
Especially, single anthracene core anthraquinone analog compound is deep red Rhein, rheum emodin, Chrysophanol, aloe-emodin, anthracene
Phenol, rubican, Physcion, Physcion -8-O- β-D-Glucose glycosides, chrysophanol-8-O-β-D-glucopyranoside,
8-O- β-D-Glucose base rheum emodin, Chrysophanol -1-O- tri-glucoses glycosides, barbaloin, 1- hydroxy-anthraquiones, 2- hydroxy-anthraquiones, 1,
8- dihydroxy anthraquinones, 2,6- dihydroxy anthraquinones, quinizarin, 2- chloroanthraquinones, 1,5- dichloroanthraquinones, 1- amino -4- bromo -2- methyl anthracenes
Any one or a few mixture in quinone, Isosorbide-5-Nitrae-diamino-anthraquinone, 1- amino-4-hydroxy anthraquinos.
By research, it has been found that the necrosis in single anthracene core anthraquinone analog compound and cardiac muscle of labelled with radioisotope is thin
Born of the same parents have very strong affinity, are have very strong affinity for the myocardial necrosis cell that heart infarction is caused especially.Therefore,
We have done substantial amounts of checking test based on this theory, show single anthracene core anthraquinone analog compound pair of labelled with radioisotope
There is specific binding affinity in myocardial necrosis cell, can largely be gathered on necrotic myocardium cell, using radio isotope
Mark, radiographic source can be produced, the purpose for reaching effective detection myocardial necrosis cell is used in combination by detector.
Because different single anthracene core anthraquinone analog compounds spatial configuration in itself has differences, and the difference on these configurations
Single anthracene core anthraquinone of single anthracene core anthraquinone or labelled with radioisotope can be influenceed affine for the targeting of necrotic myocardium cell
Power.Therefore our preferred single anthracene core anthraquinone analog compounds be Rhein, rheum emodin, Chrysophanol, aloe-emodin, anthrarufin,
Rubican, Physcion, Physcion -8-O- β-D-Glucose glycosides, chrysophanol-8-O-β-D-glucopyranoside, 8-
O- β-D-Glucose base rheum emodin, Chrysophanol -1-O- tri-glucoses glycosides, barbaloin, 1- hydroxy-anthraquiones, 2- hydroxy-anthraquiones, 1,8-
Dihydroxy anthraquinone, 2,6- dihydroxy anthraquinones, quinizarin, 2- chloroanthraquinones, 1,5- dichloroanthraquinones, 1- amino -4- bromo -2- methyl anthracenes
Quinone, Isosorbide-5-Nitrae-diamino-anthraquinone, the compound of 1- amino-4-hydroxy anthraquinos, it is high with the non-viable non-apoptotic cell affinity of cardiac muscle, targeting
Height, Detection results are more accurate.
Brief description of the drawings
Fig. 1 is TTC colored graph of the iodine -131 mark Rhein in Rat of Myocardial Infarction model；
Fig. 2 is autoradiograph of the iodine -131 mark Rhein in Rat of Myocardial Infarction model；
Fig. 3 is TTC colored graph of the iodine -131 mark rubican in Rat of Myocardial Infarction model；
Fig. 4 is autoradiograph of the iodine -131 mark rubican in Rat of Myocardial Infarction model；
Fig. 5 is that iodine -131 mark rheum emodin images figure in the SPECT-CT of Rat of Myocardial Infarction model
Specific embodiment
The material selected in following examples is as follows：
Male SD rat (purchase), single anthracene core anthraquinone analog compound be Rhein, rheum emodin, Chrysophanol, aloe-emodin,
Anthrarufin, rubican, Physcion, Physcion -8-O- β-D-Glucose glycosides, Chrysophanol -8-O- β-D- glucopyras
Glucosides, 8-O- β-D-Glucose base rheum emodin, Chrysophanol -1-O- tri-glucoses glycosides, barbaloin, 1- hydroxy-anthraquiones, 2- hydroxyl anthracenes
Quinone, 1,8- dihydroxy anthraquinones, 2,6- dihydroxy anthraquinones, quinizarin, 2- chloroanthraquinones, 1,5- dichloroanthraquinones, 1- amino -4- bromos -2-
Tectoquinone, Isosorbide-5-Nitrae-diamino-anthraquinone, 1- amino-4-hydroxy anthraquinos, activity meter, DMSO analyses are pure, and (the rich Dihua work in Tianjin is limited
Company), Iodogen reagents (sigma companies of the U.S.), concentrated hydrochloric acid analyzes pure (Nanjing Chemistry Reagent Co., Ltd.), Na iodine -131s
Solution (Beijing Atom High Tech Co., Ltd.), Na iodine-125s solution (Beijing Atom High Tech Co., Ltd.), 2,3,5-
Triphenyltetrazolium chloride (TTC, Shanghai Ling Jin Fine Chemical Co., Ltd), remaining reagent is pure, the RM-905a activity of analysis
Meter (China National Measuring Science Research Inst.'s development), SN-697 gamma counters (Shanghai He Suohuan photoelectric instruments Co., Ltd) are small
Animal respirator (Shanghai Alcott bio tech ltd), cyclone plus phosphorus screen scanners (Perkin Elmer
Company).
The NM material of the above, unless special declaration in embodiment, is otherwise ordinary commercial products.
The preparation of the Rat of Myocardial Infarction model of embodiment 1
SD rat body weight 200-300g, the chloraldurate (0.3mL/100g) of intraperitoneal injection 10%.Rat faces upward after anesthesia
It is fixed on mouse platform, oral trachea cannula connection toy lung ventilator, 60-80 beats/min of respiratory rate, respiratory quotient 1/1, tidal volume
4mL/100g.After Iodophor skin degerming, chest is opened along left border of sternum 3,4 intercostals, expose heart, pericardium is peeled off, at interventricular groove
Left auricle of heart parallel beneath threading, ligatures ramus descendens anterior arteriae coronariae sinistrae.After ligation, thoracic cavity air is extracted out, recover intrathoracic negative pressure, quickly
Suture thoracic cavity, withdraws from trachea cannula, and the U/ of intramuscular injection penicillin 160,000 is only.
The iodine -131 of embodiment 2 marks the preparation of Rhein
0.4mg Rheins are weighed, is dissolved in 182.8 μ l DMSO, vibration shakes up, and obtains 2.2mg/ml Rhein DMSO solutions.
By concentration for the μ l of Rhein DMSO solution 182.8 of 2.2mg/ml are added in the painting pipe that Iodogen contents are 40 μ g, add
The 17500 μ Ci Na iodine -131 solution of 45.7 μ l, add 15 μ l PBS, and vibration shakes up, 45 DEG C of heating responses in water-bath
90min or so, after terminating reaction, mark rate is determined with TLC methods, and mark rate is more than 95%, shows to mark successfully.Mark rate is measured
Method：Reaction solution determines mark rate with paper chromatography, and, used as carrier, 0.1mol/L HCl are used as mobile phase exhibition for Whatman filter paper
Open.Label uses paper chromatography measurement markers rate, and free 131I is distributed in solvent front, and 131I mark Rheins are protected
Stay in origin.
The iodine -131 of embodiment 3 marks distribution of the Rhein on Rat of Myocardial Infarction model
The iodine -131 mark rheum officinale acid solution that will be prepared in embodiment 2 adds PEG 400- propane diols (1: 1) dilutions.Take
Myocardial infarction model rat 6, (radiochemical purity is for every μ Ci of intravenous injection iodine -131 mark rheum officinale acid solution 100
90%).After 12h, euthanasia rat model takes each internal organs (thyroid gland, kidney, liver, spleen, lung, normal myocardium, infarct
Cardiac muscle, small intestine, stomach, muscle and fur etc.), weigh respectively and measure radioactivity with gamma counter, after decay correction, knot
The radioactive uptake that fruit is expressed as every gram of internal organs or tissue accounts for the percentage (%ID/g) of total injection dosage.
It is 0.78%ID/g in necrotic myocardium distribution values after iodine -131 mark Rhein 12h, normal myocardium is 0.15%
The distributions ratios of ID/g, necrotic myocardium and normal myocardium are 5.2 times.Blood distribution is rarely 0.062%ID/g, does not have in thyroid gland
There is specific intake.
Table 1
| Tissue or organ | %ID/g ± SD |
| Blood | 0.062±0.010 |
| Lung | 0.051±0.021 |
| Necrotic myocardium | 0.78±0.165 |
| Normal myocardium | 0.15±0.035 |
| Liver | 0.431±0.062 |
| Stomach | 0.181±0.029 |
| Spleen | 0.124±0.032 |
| Pancreas | 0.091±0.042 |
| Small intestine | 0.180±0.030 |
| Large intestine | 0.065±0.011 |
| Kidney | 0.330±0.051 |
| Bladder | 0.160±0.041 |
| Skin | 0.103±0.014 |
| Thyroid gland | 0.121±0.023 |
| Muscle | 0.031±0.007 |
| Necrotic myocardium/normal myocardium | 5.2 |
TTC dyeing and iodine -131 mark Rhein autoradiograph contrast of the embodiment 4 in Rat of Myocardial Infarction model
Take isolated heart and be made 2mm slabs, under the conditions of lucifuge with 2% 2,3,5- triphenyltetrazolium chlorides
(TTC) 37 DEG C of incubation 15min of solution.The heart sections after dyeing are taken, the photosensitive phosphorus screen exposure of high-resolution is acted at 4 DEG C of darkroom
1h, is imaged after end exposure with phosphorus screen scanner scanning.
Heart shows as brick-red by normal myocardium after 2%TTC dyeing, and necrotic myocardium is not coloured and is shown as white
Color, position shown in black circle in Fig. 1.The necrotic myocardium region and normal myocardium region of heart can be observed directly.
Autoradiograph is carried out using the iodine -131 mark Rhein prepared in embodiment 2, image display heart is not
With the increased radioactivity in region, shown in Fig. 2, i.e. distribution of the iodine -131 mark Rhein on heart, it is iodo- that both contrast discovery
131 mark Rheins can selectivity at myocardial infarction region clustering (position shown in black circle), have a common boundary in infarct and normal myocardium
Place is also distributed, and normal myocardium region is not almost distributed.
The iodine -131 of embodiment 5 marks the preparation of rubican
Weigh 1.1mg rubicans to be dissolved in 0.5ml DMSO, vibration shakes up, obtain 2.2mg/ml rubican DMSO solutions.Take
The rubican solution of the 2.2mg/ml of 500 μ l is then added in the painting pipe that Iodogen contents are 40 μ g, adds 91.5 μ l's
17500 μ Ci Na iodine -131 solution, vibration shakes up room temperature reaction 20min or so, after terminating reaction, mark rate is determined with TLC methods,
Mark rate is more than 98%, shows to mark successfully.Mark rate measuring method：Reaction solution determines mark rate, Whatman with paper chromatography
, used as carrier, 0.1mol/L HCl are used as flowing phase demodulation for filter paper.Label uses paper chromatography measurement markers rate, free
131I is distributed in solvent front, and 131I mark rubicans are retained in origin.
The iodine -131 of embodiment 6 marks distribution of the rubican in Rat of Myocardial Infarction
The iodine -131 mark rubican solution that will be prepared in embodiment 5 adds PEG 400, propane diols (1: 1) dilution.Take
Myocardial infarction model rat 6, (radiochemical purity is for every μ Ci of intravenous injection iodine -131 mark rubican solution 100
90%).After 12h, euthanasia rat model takes each internal organs (thyroid gland, kidney, liver, spleen, lung, normal myocardium, infarct
Cardiac muscle, small intestine, stomach, muscle and fur etc.), weigh respectively and measure radioactivity with gamma counter, after decay correction, knot
The radioactive uptake that fruit is expressed as every gram of internal organs or tissue accounts for the percentage (%ID/g) of total injection dosage.
Iodine -131 marks distribution results of the rubican in Rat of Myocardial Infarction, is shown in Table 2.Iodine -131 mark rubican 12h
Afterwards, it is 1.134%ID/g in necrotic myocardium distribution values, normal myocardium is 0.168%ID/g, necrotic myocardium and normal myocardium
Distributions ratios are 6.7 times.Blood distribution is rarely 0.181%ID/g, is absorbed without specificity in thyroid gland.
Table 2
| Tissue or organ | %ID/g ± SD |
| Blood | 0.181±0.028 |
| Lung | 0.076±0.013 |
| Necrotic myocardium | 1.134±0.115 |
| Normal myocardium | 0.168±0.032 |
| Liver | 0.492±0.078 |
| Stomach | 0.160±0.026 |
| Spleen | 0.199±0.017 |
| Pancreas | 0.088±0.016 |
| Small intestine | 0.093±0.030 |
| Large intestine | 0.109±0.032 |
| Kidney | 0.332±0.074 |
| Bladder | 0.141±0.027 |
| Skin | 0.127±0.029 |
| Thyroid gland | 0.043±0.016 |
| Muscle | 0.025±0.008 |
| Necrotic myocardium/normal myocardium | 6.7 |
The TTC of embodiment 7 is dyeed and iodine -131 marks rubican autoradiograph
Take isolated heart and be made 2mm slabs, under the conditions of lucifuge with 2% 2,3,5- triphenyltetrazolium chlorides
(TTC) 37 DEG C of incubation 15min of solution.The heart sections after dyeing are taken, the photosensitive phosphorus screen exposure of high-resolution is acted at 4 DEG C of darkroom
1h, is imaged after end exposure with phosphorus screen scanner scanning.
Heart shows as brick-red by normal myocardium after 2%TTC dyeing, and necrotic myocardium is not coloured and is shown as white
Color, position shown in black circle in Fig. 3 can observe directly the necrotic myocardium region and normal myocardium region of heart.
The image of autoradiograph is shown the increased radioactivity of different zones on heart, shown in Fig. 4, i.e. iodine -131 mark
Distribution of the note rubican on heart, both contrast and find the poly- in myocardial infarction region of iodine -131 mark rubican energy selectivity
Collection (position shown in black circle), is also distributed in infarct and normal myocardium intersection, and normal myocardium region is not almost distributed.
The iodine -131 of embodiment 8 marks the preparation of rheum emodin
Weigh 0.48mg rheum emodins to be dissolved in 650.84ul DMSO, vibration shakes up, obtain 0.74mg/ml rheum emodins DMSO molten
Liquid.The rheum emodin solution for taking the 0.74mg/ml of 650.84 μ l is then added in the painting pipe that Iodogen contents are 40 μ g, is added
The 960 μ Ci Na iodine -131 solution of 162.71ul, vibration shakes up, 45 DEG C of heating in water-bath, reaction 30min or so, terminates anti-
Ying Hou, mark rate is determined with TLC methods, and mark rate is more than 96%, shows to mark successfully.Mark rate measuring method：Reaction solution paper
Chromatography determines mark rate, and, used as carrier, 0.1mol/L HCl are used as flowing phase demodulation for Whatman filter paper.Label uses paper
Chromatography measurement markers rate, free 131I is distributed in solvent front, and 131I mark rheum emodins are retained in origin.
The iodine -131 of embodiment 9 marks distribution of the rheum emodin in Rat of Myocardial Infarction
The iodine -131 mark rheum emodin solution that will be prepared in embodiment 8 adds PEG 400- propane diols (1: 1) dilutions.Take
Myocardial infarction model rat 6, (radiochemical purity is for every μ Ci of intravenous injection iodine -131 mark rheum emodin solution 100
90%).SPECT-CT is scanned after 12h, euthanasia rat model after scanning takes each internal organs (thyroid gland, kidney, liver, spleen
Dirty, lung, normal myocardium, infarcted myocardium, small intestine, stomach, muscle and fur etc.), weigh respectively and measured with gamma counter and radiate
Activity, through decay correction after, the radioactive uptake for being as a result expressed as every gram of internal organs or tissue accounts for the percentage (% of total injection dosage
ID/g)。
Iodine -131 marks distribution results of the rheum emodin in Rat of Myocardial Infarction, is shown in Table 3.Iodine -131 mark rheum emodin 12h
Afterwards, it is 2.310%ID/g in necrotic myocardium distribution values, normal myocardium is 0.520%ID/g, necrotic myocardium and normal myocardium
Distributions ratios are 4.4 times.Blood distribution is rarely 0.097%ID/g, is absorbed without specificity in thyroid gland.
Table 3
| Tissue or organ | %ID/g ± SD |
| Blood | 0.097±0.009 |
| Lung | 0.103±0.013 |
| Necrotic myocardium | 2.310±0.015 |
| Normal myocardium | 0.520±0.009 |
| Liver | 0.591±0.014 |
| Stomach | 0.134±0.036 |
| Spleen | 0.283±0.037 |
| Pancreas | 0.192±0.041 |
| Small intestine | 0.129±0.043 |
| Large intestine | 0.139±0.018 |
| Kidney | 0.181±0.052 |
| Bladder | 0.159±0.011 |
| Skin | 0.099±0.014 |
| Thyroid gland | 0.127±0.014 |
| Muscle | 0.035±0.005 |
| Necrotic myocardium/normal myocardium | 4.4 |
The iodine -131 of embodiment 10 marks image results of the rheum emodin in Rat of Myocardial Infarction
After injection iodine -131 mark rheum emodin 12h, the SPECT-CT image results of myocardial infarction and normal rat are shown in figure
5.As seen from Figure 5：There is obvious radioactivity concentration at 12h after injection, the heart infarction position of Rat of Myocardial Infarction, referring specifically to figure
Position shown in arrow in 5B；Lung has no obvious radioactivity concentration.And the "dead" concentration of cardia of normal rat, can join
See Fig. 5 A corresponding parts.
The iodine-125 of embodiment 11 marks the preparation of Chrysophanol
Weigh 0.50mg Chrysophanols to be dissolved in 500.00ul DMSO, vibration shakes up, obtain 1.0mg/ml Chrysophanols DMSO molten
Liquid.The rheum officinale phenol solution for taking the 1.0mg/ml of 500.00 μ l is then added in the painting pipe that Iodogen contents are 40 μ g, is added
The 960 μ Ci Na iodine-125 solution of 125.71ul, add 30 μ l PBS, and vibration shakes up 45 DEG C of heating in water-bath, reacts 2h
Left and right, after terminating reaction, mark rate is determined with TLC methods, and mark rate is more than 90%, shows to mark successfully.Mark rate measuring method：
Reaction solution paper chromatography determines mark rate, and, used as carrier, 0.1mol/L HCl are used as flowing phase demodulation for Whatman filter paper.Mark
Note thing uses paper chromatography measurement markers rate, and free 125I is distributed in solvent front, and 125I mark Chrysophanols are retained in
Origin.
The iodine-125 of embodiment 12 marks distribution of the Chrysophanol in Rat of Myocardial Infarction
The iodine-125 mark rheum officinale phenol solution that will be prepared in embodiment 11 adds PEG 400- propane diols (1: 1) dilutions.
Take myocardial infarction model rat 6, (radiochemical purity is for every μ Ci of intravenous injection iodine-125 mark rheum officinale phenol solution 100
90%).After 12h, euthanasia rat model takes each internal organs (thyroid gland, kidney, liver, spleen, lung, normal myocardium, infarct
Cardiac muscle, small intestine, stomach, muscle and fur etc.), weigh respectively and measure radioactivity with gamma counter, after decay correction, knot
The radioactive uptake that fruit is expressed as every gram of internal organs or tissue accounts for the percentage (%ID/g) of total injection dosage.
Iodine-125 marks distribution results of the Chrysophanol in Rat of Myocardial Infarction, is shown in Table 4.Iodine-125 mark Chrysophanol 12h
Afterwards, it is 0.867%ID/g in necrotic myocardium distribution values, normal myocardium is 0.177%ID/g, necrotic myocardium and normal myocardium
Distributions ratios are 4.9 times.Blood distribution is rarely 0.103%ID/g, is absorbed without specificity in thyroid gland.
Table 4
| Tissue or organ | %ID/g ± SD |
| Blood | 0.103±0.007 |
| Lung | 0.099±0.010 |
| Necrotic myocardium | 0.867±0.017 |
| Normal myocardium | 0.177±0.037 |
| Liver | 0.592±0.018 |
| Stomach | 0.091±0.014 |
| Spleen | 0.244±0.019 |
| Pancreas | 0.152±0.029 |
| Small intestine | 0.126±0.023 |
| Large intestine | 0.157±0.016 |
| Kidney | 0.191±0.025 |
| Bladder | 0.182±0.017 |
| Skin | 0.116±0.009 |
| Thyroid gland | 0.110±0.014 |
| Muscle | 0.038±0.005 |
| Necrotic myocardium/normal myocardium | 4.9 |
The iodine -131 of embodiment 13 marks the preparation of aloe-emodin
0.8mg aloe-emodins are weighed, is dissolved in 400.00 μ l DMSO, vibration shakes up, and obtains 2.0mg/ml aloe-emodins
DMSO solution.It is 40 μ g that the μ l of aloe-emodin DMSO solution 400.0 that concentration is 2.0mg/ml are added into Iodogen contents
Tu Guanzhong, adds the 17500 μ Ci Na iodine -131 solution of 100.0 μ l, adds 20 μ l PBS, and vibration is shaken up 60 DEG C in water-bath
Heating, reaction 2h or so, after terminating reaction, mark rate are determined with TLC methods, and mark rate is more than 94%, shows to mark successfully.Mark
Rate measuring method：Reaction solution determines mark rate with paper chromatography, and, used as carrier, 0.1mol/L HCl are used as stream for Whatman filter paper
Dynamic phase demodulation.Label uses paper chromatography measurement markers rate, and free 131I is distributed in solvent front, and 131I mark reeds
Luxuriant growth rheum emodin is retained in origin.
The iodine -131 of embodiment 14 marks distribution of the aloe-emodin on Rat of Myocardial Infarction model
The iodine -131 mark aloe-emodin solution that will be prepared in embodiment 13 adds PEG 400, and propane diols (1: 1) is dilute
Release.Take myocardial infarction model rat 6, every μ Ci (radiochemistry of intravenous injection iodine -131 mark aloe-emodin solution 100
90%) purity be.After 12h, euthanasia rat model takes each internal organs (thyroid gland, kidney, liver, spleen, lung, the normal heart
Flesh, infarcted myocardium, small intestine, stomach, muscle and fur etc.), weigh respectively and measure radioactivity with gamma counter, through school of decaying
After just, the radioactive uptake for being as a result expressed as every gram of internal organs or tissue accounts for the percentage (%ID/g) of total injection dosage.
It is 0.477%ID/g in necrotic myocardium distribution values after iodine -131 mark aloe-emodin 12h, normal myocardium is
The distributions ratios of 0.090%ID/g, necrotic myocardium and normal myocardium are 5.3 times.Blood distribution is rarely 0.260%ID/g, first
Absorbed without specificity in shape gland.
Table 5
| Tissue or organ | %ID/g ± SD |
| Blood | 0.260±0.006 |
| Lung | 0.081±0.014 |
| Necrotic myocardium | 0.477±0.104 |
| Normal myocardium | 0.090±0.001 |
| Liver | 0.391±0.024 |
| Stomach | 0.201±0.037 |
| Spleen | 0.116±0.019 |
| Pancreas | 0.088±0.036 |
| Small intestine | 0.194±0.035 |
| Large intestine | 0.055±0.012 |
| Kidney | 0.297±0.035 |
| Bladder | 0.179±0.039 |
| Skin | 0.101±0.007 |
| Thyroid gland | 0.111±0.012 |
| Muscle | 0.057±0.008 |
| Necrotic myocardium/normal myocardium | 5.3 |
The iodine -131 of embodiment 15 marks the preparation of anthrarufin
0.25mg anthrarufins are weighed, is dissolved in 125.0 μ l DMSO, vibration shakes up, and obtains 2.0mg/ml anthrarufins DMSO molten
Liquid.By concentration for the μ l of anthrarufin DMSO solution 125.0 of 2.0mg/ml are added to the painting pipe for preparing that Iodogen contents are 40 μ g
In, the 17500 μ Ci Na iodine -131 solution of 35.7 μ l are added, vibration shakes up 45 DEG C of heating in water-bath, reaction 30min or so,
After terminating reaction, mark rate is determined with TLC methods, mark rate is more than 97%, shows to mark successfully.Mark rate measuring method：Reaction
Liquid paper chromatography determines mark rate, and, used as carrier, 0.1mol/L HCl are used as flowing phase demodulation for Whatman filter paper.Label
Using paper chromatography measurement markers rate, free 131I is distributed in solvent front, and 131I mark anthrarufins are retained in origin.
The iodine -131 of embodiment 16 marks distribution of the anthrarufin on Rat of Myocardial Infarction model
The iodine -131 mark anthrarufin solution that will be prepared in embodiment 15 adds PEG 400, propane diols (1: 1) dilution.
Take myocardial infarction model rat 6, (radiochemical purity is for every μ Ci of intravenous injection iodine -131 mark anthrarufin solution 100
90%).After 12h, euthanasia rat model takes each internal organs (thyroid gland, kidney, liver, spleen, lung, normal myocardium, infarct
Cardiac muscle, small intestine, stomach, muscle and fur etc.), weigh respectively and measure radioactivity with gamma counter, after decay correction, knot
The radioactive uptake that fruit is expressed as every gram of internal organs or tissue accounts for the percentage (%ID/g) of total injection dosage.
It is 1.093%ID/g in necrotic myocardium distribution values after iodine -131 mark anthrarufin 12h, normal myocardium is
The distributions ratios of 0.185%ID/g, necrotic myocardium and normal myocardium are 5.9 times.Blood distribution is rarely 0.106%ID/g, first
Absorbed without specificity in shape gland.
Table 6
| Tissue or organ | %ID/g ± SD |
| Blood | 0.106±0.002 |
| Lung | 0.096±0.037 |
| Necrotic myocardium | 1.093±0.015 |
| Normal myocardium | 0.185±0.028 |
| Liver | 0.371±0.026 |
| Stomach | 0.174±0.020 |
| Spleen | 0.153±0.015 |
| Pancreas | 0.081±0.036 |
| Small intestine | 0.183±0.031 |
| Large intestine | 0.068±0.017 |
| Kidney | 0.325±0.028 |
| Bladder | 0.153±0.027 |
| Skin | 0.132±0.025 |
| Thyroid gland | 0.119±0.017 |
| Muscle | 0.024±0.005 |
| Necrotic myocardium/normal myocardium | 5.9 |
The iodine -131 of embodiment 17 marks the preparation of Isosorbide-5-Nitrae-diamino-anthraquinone
0.4mgl is weighed, 4- diamino-anthraquinones are dissolved in 210.8 μ l DMSO, and vibration shakes up, and obtains 1.9mg/ml1,4- bis-
Amino anthraquinones DMSO solution.Concentration is prepared for the μ l of Isosorbide-5-Nitrae-diamino-anthraquinone DMSO solution 210.8 of 1.9mg/ml are added to
During Iodogen contents are the painting pipe of 40 μ g, the 17500 μ Ci Na iodine -131 solution of 58.7 μ l are added, vibration is shaken up in water-bath
60 DEG C of heating, reaction 90min or so, after terminating reaction, mark rate are determined with TLC methods, and mark rate is more than 94%, shows to be marked as
Work(.Mark rate measuring method：Reaction solution determines mark rate with paper chromatography, and Whatman filter paper is used as carrier, 0.1mol/L HCl
As flowing phase demodulation.Label uses paper chromatography measurement markers rate, and free 131I is distributed in solvent front, and 131I
Mark Isosorbide-5-Nitrae-diamino-anthraquinone is retained in origin.
The iodine -131 of embodiment 18 marks distribution of the Isosorbide-5-Nitrae-diamino-anthraquinone on Rat of Myocardial Infarction model
The iodine -131 mark Isosorbide-5-Nitrae that will be prepared in embodiment 17-diamino-anthraquinone solution addition PEG 400, propane diols (1:
1) dilute.Take myocardial infarction model rat 6, every intravenous injection iodine -131 mark Isosorbide-5-Nitrae-diamino-anthraquinone solution 100 μ Ci
(radiochemical purity is 90%).After 12h, euthanasia rat model, take each internal organs (thyroid gland, kidney, liver, spleen,
Lung, normal myocardium, infarcted myocardium, small intestine, stomach, muscle and fur etc.), weigh respectively and measure radiation with gamma counter and live
Property, through decay correction after, the radioactive uptake for being as a result expressed as every gram of internal organs or tissue accounts for the percentage (% of total injection dosage
ID/g)。
It is 0.976%ID/g, the normal heart in necrotic myocardium distribution values after iodine -131 mark Isosorbide-5-Nitrae-diamino-anthraquinone 12h
Flesh is 0.238%ID/g, and the distributions ratios of necrotic myocardium and normal myocardium are 4.1 times.Blood distribution is rarely 0.064%ID/
G, absorbs in thyroid gland without specificity.
Table 7
| Tissue or organ | %ID/g ± SD |
| Blood | 0.064±0.012 |
| Lung | 0.082±0.017 |
| Necrotic myocardium | 0.976±0.018 |
| Normal myocardium | 0.238±0.024 |
| Liver | 0.370±0.027 |
| Stomach | 0.183±0.012 |
| Spleen | 0.164±0.023 |
| Pancreas | 0.151±0.051 |
| Small intestine | 0.219±0.025 |
| Large intestine | 0.055±0.003 |
| Kidney | 0.402±0.036 |
| Bladder | 0.164±0.027 |
| Skin | 0.118±0.019 |
| Thyroid gland | 0.119±0.015 |
| Muscle | 0.026±0.009 |
| Necrotic myocardium/normal myocardium | 4.1 |
The iodine -131 of embodiment 19 marks the preparation of 1- amino-4-hydroxy anthraquinos
0.4mg1- amino-4-hydroxy anthraquinos are weighed, is dissolved in 400.0 μ l DMSO, vibration shakes up, and obtains 1.0mg/ml1- ammonia
Base -4- hydroxy-anthraquione DMSO solutions.By concentration for the μ l of 1- amino-4-hydroxy anthraquinos DMSO solution 400.0 of 1.0mg/ml are added
To in preparing the painting pipe that Iodogen contents are 40 μ g, the 17500 μ Ci Na iodine -131 solution of 100.0 μ l are added, vibration shakes up
60 DEG C of heating in water-bath, reaction 90min or so, after terminating reaction, mark rate are determined with TLC methods, and mark rate is more than 90%, table
It is bright to mark successfully.Mark rate measuring method：Reaction solution with paper chromatography determine mark rate, Whatman filter paper as carrier,
0.1mol/L HCl are used as flowing phase demodulation.Label uses paper chromatography measurement markers rate, and free 131I is distributed in molten
Agent forward position, and 131I mark 1- amino-4-hydroxy anthraquinos are retained in origin.
The iodine -131 of embodiment 20 marks distribution of the 1- amino-4-hydroxy anthraquinos on Rat of Myocardial Infarction model
The iodine -131 mark 1- amino-4-hydroxy anthraquinos solution that will be prepared in embodiment 19 adds PEG 400, propane diols
(1: 1) dilute.Take myocardial infarction model rat 6, every intravenous injection iodine -131 mark 1- amino-4-hydroxy anthraquino solution
100 μ Ci (radiochemical purity is 90%).After 12h, euthanasia rat model, take each internal organs (thyroid gland, kidney, liver,
Spleen, lung, normal myocardium, infarcted myocardium, small intestine, stomach, muscle and fur etc.), weigh respectively and put with gamma counter measurement
Penetrate activity, through decay correction after, the radioactive uptake for being as a result expressed as every gram of internal organs or tissue accounts for the percentage of total injection dosage
(%ID/g).
It is 0.788%ID/g in necrotic myocardium distribution values, normally after iodine -131 mark 1- amino-4-hydroxy anthraquinos 12h
Cardiac muscle is 0.175%ID/g, and the distributions ratios of necrotic myocardium and normal myocardium are 4.5 times.Blood distribution is rarely 0.034%
ID/g, absorbs in thyroid gland without specificity.
Table 8
| Tissue or organ | %ID/g ± SD |
| Blood | 0.034±0.003 |
| Lung | 0.064±0.026 |
| Necrotic myocardium | 0.788±0.163 |
| Normal myocardium | 0.175±0.022 |
| Liver | 0.262±0.017 |
| Stomach | 0.142±0.014 |
| Spleen | 0.141±0.012 |
| Pancreas | 0.053±0.022 |
| Small intestine | 0.199±0.024 |
| Large intestine | 0.073±0.027 |
| Kidney | 0.472±0.023 |
| Bladder | 0.152±0.021 |
| Skin | 0.897±0.012 |
| Thyroid gland | 0.102±0.016 |
| Muscle | 0.036±0.009 |
| Necrotic myocardium/normal myocardium | 4.5 |
According to the mode in embodiment 1 to 20, respectively to technetium -99, ytterbium -111, ytterbium -113, Value linear, iodo- 123 and iodo-
Single anthracene core anthraquinone analog compound of 124 marks carries out targeting focusing experiment, it is found that it has essentially identical with embodiment
Therefore targeting, can be equally used for preparing the medicine for detecting myocardial activity.
Claims (7)
1. single anthracene core anthraquinone analog compound of labelled with radioisotope is being prepared for the application in myocardial activity detection medicine.
2. application according to claim 1, it is characterized in that：Single anthracene core anthraquinone analog compound of labelled with radioisotope exists
Prepare for the application in myocardial activity detection developer.
3. application according to claim 2, it is characterized in that：Single anthracene core anthraquinone analog compound of labelled with radioisotope exists
Prepare for the application in myocardial infarction class myocardial activity detection developer.
4. according to the application in claim 1 or 2 or described in 3, it is characterized in that：The radio isotope be iodo- 123, it is iodo-
124th, iodine-125, iodine -131, technetium -99, Value linear, ytterbium -111 or ytterbium -113.
5. the application according to any one in claim 1 or 2 or 3, it is characterized in that：Single anthracene core anthraquinone analog compound
It is rheum emodin type list anthracene core anthraquinone analog compound.
6. the application according to any one in claim 1 or 2 or 3, it is characterized in that：Single anthracene core anthraquinone analog compound
It is rubican type list anthracene core anthraquinone analog compound.
7. the application according to any one in claim 1 or 2 or 3, it is characterized in that：Single anthracene core anthraquinone analog compound
For Rhein, rheum emodin, Chrysophanol, aloe-emodin, anthrarufin, rubican, Physcion, Physcion -8-O- β -
D-Glucose glycosides, chrysophanol-8-O-β-D-glucopyranoside, 8-O- β-D-Glucose base rheum emodin, the Portugals of Chrysophanol -1-O- three
Polyglycoside, barbaloin, 1- hydroxy-anthraquiones, 2- hydroxy-anthraquiones, 1,8- dihydroxy anthraquinones, 2,6- dihydroxy anthraquinones, quinizarin, 2- chrloroanthracenes
In quinone, 1,5- dichloroanthraquinones, 1- amino -4- bromos -2-methylanthraquinone, Isosorbide-5-Nitrae-diamino-anthraquinone, 1- amino-4-hydroxy anthraquinos
Any one or a few mixture.
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| WO1992007557A1 (en) * | 1990-11-02 | 1992-05-14 | Spinx Pharmaceuticals Corporation | Bis-(hydroxyalkylamino)-anthraquinone inhibitors of protein kinase c |
| CN103341185A (en) * | 2013-07-23 | 2013-10-09 | 江苏省中医药研究院 | Application of radioisotope-labeled meso-position dianthrone compound in preparation of drug for detecting myocardial activity |
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| WO1992007557A1 (en) * | 1990-11-02 | 1992-05-14 | Spinx Pharmaceuticals Corporation | Bis-(hydroxyalkylamino)-anthraquinone inhibitors of protein kinase c |
| CN103341185A (en) * | 2013-07-23 | 2013-10-09 | 江苏省中医药研究院 | Application of radioisotope-labeled meso-position dianthrone compound in preparation of drug for detecting myocardial activity |
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