CN107875405A - Application of the labelled with radioisotope naphthoquinone compound in necrotic myocardium imaging - Google Patents
Application of the labelled with radioisotope naphthoquinone compound in necrotic myocardium imaging Download PDFInfo
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- CN107875405A CN107875405A CN201610878130.4A CN201610878130A CN107875405A CN 107875405 A CN107875405 A CN 107875405A CN 201610878130 A CN201610878130 A CN 201610878130A CN 107875405 A CN107875405 A CN 107875405A
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- KETQAJRQOHHATG-UHFFFAOYSA-N O=C(C=Cc1c2cccc1)C2=O Chemical compound O=C(C=Cc1c2cccc1)C2=O KETQAJRQOHHATG-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to drug field, more particularly to the application field of naphthoquinone compound, more particularly relates to application of the naphthoquinone compound of labelled with radioisotope in the developer for preparing necrotic myocardium imaging.The present invention, to the specific binding affinity of necrotic myocardium, can realize the purpose of effective detection necrotic myocardium, so as to have found a kind of reliable necrotic myocardium fast imaging tracer using the naphthoquinone compound of labelled with radioisotope with reference to the use of detector.
Description
Technical field
The present invention relates to drug field, more particularly to the application field of naphthoquinone compound, more specifically relates to
And application of the naphthoquinone compound of labelled with radioisotope in necrotic myocardium imagewise development agent is prepared.
Background technology
Cardiovascular disease turns into " the first killer " for threatening human life and health, and coronary heart disease is " arch-criminal ".Blood
Pipe reconstruction technique can be directed to myocardial ischemia, hence it is evident that improve left room systolic and diastolic function, improve patient's survival rate.But blood fortune weight
Build and be not suitable for all patients with coronary heart disease.The patient that a large amount of irreversible necrotic myocardiums have been formed for myocardial ischemia area is transported using blood
It Reconstruction, can not only accelerate the death of patient because of reperfusion injury, and high medical expense need to be undertaken.Therefore, to hat
Cardiaopath should carry out myocardial activity evaluation using reconstructing blood vessel is preoperative, so as to instruct the reasonable selection of coronary heart disease treatment scheme,
Avoid risk caused by the treatment of blindness revascularization.
At present, Non-Invasive myocardial imaging is the important means for evaluating myocardial activity.Most of tracers are being deposited according to it
The absorption of myocardial region living is assessed myocardial activity.18F-FDG PET imagings are the goldstandards of myocardial activity evaluation, typically
It is combined with myocardial perfusion imaging, energy reflecting myocardium metaboilic level and perfusion situation, the cardiac muscle of survival can be carried out to quantify to divide
Analysis, but it is easily influenceed by metabolism environment especially plasma insulin and free fatty acid levels.The most frequently used SPECT contrasts
Agent99mTc-MIBI by living cells by absorbing reflecting myocardium cell viability, but it is influenceed very big, no blood area intake by CBF
Reduce or without intake, cannot be distinguished from dead cardiac muscle, and due to being incorporated on the albumen of myocardial mitochondria, may influence just
Normal myocardial function.Therefore, the imaging diagnosis clinical practice for survival myocardium is limited.
In recent years, it is a kind of new diagnosis thinking to necrotic myocardium imaging in evaluation myocardial activity.Slough compatibility
Compound is the reagent of a kind of target spot specific binding with non-viable non-apoptotic cell exposure, and the downright bad heart can be accurately positioned after connecting tracer
Flesh, assess myocardial activity.99mTc-pyrophosphate、111Both tracers of In-antimyosin are used for necrotic myocardium
The research of imaging, but because it can not be limited to clinic in the higher targeting of heart infarction early formation-background ratio.Therefore, energy is found
The tracer for enough carrying out necrotic myocardium fast imaging is significant.
The content of the invention
We have found that naphthoquinone compound, is a kind of stronger slough compatibility compound.Compared to dianthracene core class
Compound such as hypericin (the .Eur Heart such as Fonge, H. J 2008,29,260-269.), former hypericin (Liu, X.
Deng .J Drug Target 2015,23,417-426.), monokaryon anthraquinone is bad because that can be significantly improved with faster plasma clearance
Give up the idea flesh image taking speed (.Sci such as Wang, Q. Rep 2016,6,21341.).Accordingly, simplified quinones plasma clearance
Accelerate, necrotic myocardium can be accelerated to be imaged.
Based on this, the invention discloses the naphthoquinone compound of labelled with radioisotope to prepare necrotic myocardium imaging aobvious
Application in shadow agent.
The radio isotope be preferably iodo- 123, iodine-125, iodo- 124, iodine -131, technetium -99m, ytterbium -111, ytterbium -
113m, Value linear, gallium-68, copper -64, Rubidium-86.
Naphthoquinone compound of the present invention refers to compound shown in formula I and their derivative, or its pharmacy
Upper acceptable salt：
Wherein, the R in Formulas I1、R2It is selected from independently and arbitrarily：-H、-OH、-OCH3、-OC2H5、-NH2、-COOH、-
COOCH3、-COOC2H5、-CH3,-Cl ,-Br ,-CN, and R1、R2To be monosubstituted or disubstituted.
Meanwhile naphthoquinone compound of the present invention can be also the shown compounds of formula I ' or its is pharmaceutically acceptable
Salt：
Wherein, in Formulas I ' middle R1、R2It is selected from independently and arbitrarily：-H、-OH、-OCH3、-OC2H5、-NH2、-COOH、-
COOCH3、-COOC2H5、-CH3,-Cl ,-Br ,-CN, and R1、R2To be monosubstituted or disubstituted.
Also, in the present invention we it is also preferred that naphthoquinone compound be compound shown in formula I " or its pharmacy
Upper acceptable salt：
Wherein, " the middle R in Formulas I1、R2It is selected from independently and arbitrarily：-H、-OH、-OCH3、-OC2H5、-NH2、-COOH、-
COOCH3、-COOC2H5、-CH3,-Cl ,-Br ,-CN, and R1、R2To be monosubstituted or disubstituted.
Especially, preferred naphthoquinone compound refers to there is following structure in the Formulas I described in us or Formulas I ' or Formulas I "
Compound：
There is stronger affinity by studying the naphthoquinone compound for finding labelled with radioisotope and slough,
Necrotic myocardium tissue has stronger affinity for caused by heart infarction in particular.Therefore, we are done based on this theory
Substantial amounts of checking test, show the naphthoquinone compound of labelled with radioisotope has specific binding for necrotic myocardium
Power, necrotic myocardium region can be largely gathered in, using radioisotopic mark, radiographic source can be produced, pass through detection
The combined use of device reaches the purpose of effective detection necrotic myocardium.
Due to the difference of different naphthoquinone compound substituted radicals, and different substituents can influence naphthoquinones or put
Targeting affinity of the naphthoquinones of injectivity isotope mark for necrotic myocardium.Therefore our preferred naphthoquinone compounds are naphthalene
Madder, juglone, 5- methoxyl groups -2-MNQ, 1,4-naphthoquinone, menadione, plumbagin, 1,2- naphthoquinones, 4- amino -
Chloro- 1, the 2- naphthoquinones of 1,2- naphthoquinones, 4-, 1,5- naphthoquinones, bromo- 1, the 5- naphthoquinones of 4,8- diaminourea -2-, 4,8- diaminourea -2,6- bis- are bromo-
1,5- naphthoquinones (Formula II~Formula X III compounds), it is high with the non-viable non-apoptotic cell affinity of cardiac muscle, and targeting is high, and Detection results are more
Precisely.
Naphthoquinone compound is mainly used in research (Wellington, the K.W.Res of antitumor activity in the prior art
Advances 2015,5,20309-20338；The .Bioorg Med such as Bhasin, D. Chem 2013,21,4662-4669.).
There is not yet someone reports that relevant naphthoquinone compound has the dead property of targeting.The present invention is originally disclosed by radioactivity
The naphthoquinone compound of isotope marks can be used in preparing necrotic myocardium developer, and this is for the further of naphthoquinone compound
Further investigate and utilize significant.
Brief description of the drawings
Fig. 1 is the TTC colored graphs that iodine -131 marks naphthazarin compound in Rat of Myocardial Infarction model；
Fig. 2 is the autoradiograph that iodine -131 marks naphthazarin compound in Rat of Myocardial Infarction model；
Fig. 3 is the TTC colored graphs that iodine -131 marks English walnut naphtoquinone compounds in Rat of Myocardial Infarction model；
Fig. 4 is the autoradiograph that iodine -131 marks English walnut naphtoquinone compounds in Rat of Myocardial Infarction model；
Fig. 5 is that iodine -131 marks naphthazarin compound to image figure in the SPECT-CT of Rat of Myocardial Infarction model.
Embodiment
In order to preferably illustrate the present invention, below we in conjunction with specific embodiments come to the present invention further said
It is bright.
Used equipment and reagent are as follows in an embodiment of the present invention：Male SD rat (is bought from Shanghai Si Laike
Experimental animal Co., Ltd), naphthazarin, juglone, 5- methoxyl groups -2-MNQ, 1,4-naphthoquinone, menadione, Plumbago zeylanica
Quinone, 1,2- naphthoquinones, 4- amino -1,2- naphthoquinones, chloro- 1, the 2- naphthoquinones of 4-, 1,5- naphthoquinones, bromo- 1, the 5- naphthoquinones of 4,8- diaminourea -2-,
4,8- diaminourea -2,6-, bis- bromo- 1,5- naphthoquinones (Formula II~Formula X III compounds) reagent (the huge excellent limited public affairs of equipment science in Nanjing
Department).Iodogen reagents (sigma companies of the U.S.), concentrated hydrochloric acid analyze pure (Nanjing Chemistry Reagent Co., Ltd.), Na131I solution
(Beijing Atom High Tech Co., Ltd.), 2,3,5- triphenyltetrazolium chlorides (TTC, the limited public affairs of Shanghai Ling Jin fine chemistry industries
Department), remaining reagent is that analysis is pure.RM-905a activity meters (China National Measuring Science Research Inst.'s development), SN-697 gamma counters
(Shanghai He Suohuan photoelectric instruments Co., Ltd), cyclone plus phosphorus screens scanner (Perkin Elmer companies), petty action
Thing lung ventilator (Shanghai Alcott bio tech ltd).NM material above, unless special declaration in embodiment,
Otherwise it is ordinary commercial products.
The preparation of the Rat of Myocardial Infarction model of embodiment 1
SD rat body weight 200-300g, 10% chloraldurate (0.3mL/100g) is injected intraperitoneally.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, open chest with the 4th intercostal for the 3rd along left border of sternum, exposure heart, peel off pericardium,
Left auricle of heart parallel beneath threads at interventricular groove, ligatures ramus descendens anterior arteriae coronariae sinistrae.After ligation, thoracic cavity air is extracted out, recover chest
Chamber negative pressure, rapid suture thoracic cavity, trachea cannula is withdrawn from, intramuscular injection penicillin 80000U/ is only.
The preparation of the naphthazarin compound of the iodine -131 of embodiment 2 mark
1mg naphthazarin compounds (powdered) to be marked are weighed, are dissolved in 10mL DMSO, vibration shakes up, and obtains concentration
For 0.1mg/mL solution.400 μ L 0.1mg/mL naphthazarin solution are taken to be added to the painting pipe for preparing that Iodogen contents are 100 μ g
In, 100 μ L of addition 2mCi Na131I solution and 30 μ L PBS solutions (pH=7.40), vibration shakes up, and in water-bath (48
DEG C) in heat, reaction 30min or so, reaction solution is taken out, terminating reaction.Mark rate is determined with TLC methods, Whatman filter paper is made
For carrier, 0.1mol/L HCl are as flowing phase demodulation.
Distribution of the naphthazarin compound of the iodine -131 of embodiment 3 mark on Rat of Myocardial Infarction model
The naphthazarin solution of the iodine -131 prepared in embodiment 2 mark is added into PEG 400, propane diols (1: 1) dilution.Take
Myocardial infarction model rat 6, (radiochemical purity is the μ Ci of naphthazarin solution 100 of every intravenous injection iodine -131 mark
97%).After 3h, euthanasia rat model, take each internal organs (blood, thyroid gland, lung, spleen, stomach, small intestine, large intestine, kidney, bladder,
Bone, liver, brain, survival myocardium, necrotic myocardium etc.), weigh respectively and measure radioactivity with gamma counter, through decay correction
Afterwards, 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 0.35 ± 0.03%ID/g in necrotic myocardium distribution values, normally after the naphthazarin compound 3h of iodine -131 mark
Cardiac muscle is 0.03 ± 0.02%ID/g, and the distributions ratios of necrotic myocardium and normal myocardium are 11.67 times, there is good necrotic myocardium
Targeting ability.The compound blood uptake values are 0.19 ± 0.02%ID/g simultaneously, and plasma clearance quickly, has fast imaging downright bad
The potentiality of cardiac muscle.Kidney has obvious high distribution, illustrates that the compound mainly passes through renal metabolism.
Table 1131Biodistribution data of the naphthazarin compound of I marks in model mouse body
| Tissue or organ | %ID/g ± SD |
| Blood | 0.19±0.22 |
| Thyroid gland | 0.20±0.01 |
| Lung | 0.08±0.01 |
| Spleen | 0.04±0.01 |
| Stomach | 0.12±0.05 |
| Small intestine | 0.07±0.01 |
| Large intestine | 0.09±0.03 |
| Kidney | 0.79±0.21 |
| Bladder | 0.28±0.12 |
| Bone | 0.04±0.00 |
| Liver | 0.12±0.04 |
| Brain | 0.01±0.00 |
| Survival myocardium | 0.03±0.02 |
| Necrotic myocardium | 0.35±0.03 |
| Necrotic myocardium/normal myocardium | 11.67 |
The TTC dyeing of the Rat of Myocardial Infarction model of embodiment 4 and the naphthazarin compound autoradiograph pair of iodine -131 mark
Than
Take isolated heart to 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
30min, imaged with phosphorus screen scanner scanning after end exposure.
Heart normal myocardium after 2%TTC is dyed shows as brick-red, and necrotic myocardium does not have coloring to be shown as white
Color, Fig. 1 can observe directly the necrotic myocardium region (white is shown as in Fig. 1) of heart and normal myocardium region (shows in Fig. 1
It is shown as grey).
The naphthazarin compound marked using the iodine -131 being prepared in embodiment 2 carries out autoradiograph, and Fig. 2 shows the heart
Distribution of the naphthazarin compound of the increased radioactivity of dirty different zones, i.e. iodine -131 mark on heart, it is iodo- that both contrast discovery
The naphthazarin compound of 131 marks can be optionally in myocardial necrosis region clustering, and normal myocardium region is not almost distributed.
Image results of the naphthazarin compound of the iodine -131 of embodiment 5 mark in Rat of Myocardial Infarction
After intravenous iodine -131 mark naphthazarin compound 3h, Rat of Myocardial Infarction and normal rat carry out SPECT/CT into
Picture.As seen from Figure 5：3h after administration, heart infarction rat model cardia has obvious radioactivity concentration, referring specifically to Fig. 5 B
Position shown in middle arrow, habitat are shown as white.Normal rat cardiac muscle has no obvious radioactivity aggregation, can be corresponding referring to Fig. 5 A
Part, it is believed that black gray expandable.Illustrate its plasma clearance speed, embody iodine -131 mark naphthazarin compound it is good inside
Distribution and pharmacokinetic property, it is adapted to the Fast Evaluation of myocardial activity.
The preparation of the English walnut naphtoquinone compounds of the iodine -131 of embodiment 6 mark
1mg English walnut naphtoquinone compounds (powdered) to be marked are weighed, are dissolved in 10mL DMSO, vibration shakes up, and obtains dense
Spend the solution for 0.1mg/mL.Take 400 μ L 0.1mg/mL juglone solution to be added to and prepare Iodogen contents as 100 μ g's
Tu Guanzhong, add 100 μ L 2mCi Na131I solution and 20 μ L PBS solutions (pH=7.40), vibration shakes up, and in water-bath
Heat, reaction 20min or so, reaction solution is taken out, terminating reaction in pot (48 DEG C).Mark rate, Whatman are determined with TLC methods
Filter paper is as carrier, and 0.1mol/L HCl are as flowing phase demodulation.
Distribution of the English walnut naphtoquinone compounds of the iodine -131 of embodiment 7 mark in Rat of Myocardial Infarction
The iodine -131 prepared in embodiment 6 mark juglone solution is added into PEG 400, propane diols (1: 1) dilution.Take
Myocardial infarction model rat 6, (radiochemical purity is the μ Ci of juglone solution 100 of every intravenous injection iodine -131 mark
96%).After 3h, euthanasia rat model, take each internal organs (blood, thyroid gland, lung, spleen, stomach, small intestine, large intestine, kidney, bladder,
Bone, liver, brain, survival myocardium, necrotic myocardium etc.), weigh respectively and measure radioactivity with gamma counter, through decay correction
Afterwards, 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.
Distribution results of the English walnut naphtoquinone compounds of iodine -131 mark in Rat of Myocardial Infarction, are shown in Table 2.Iodine -131 mark
It is 0.72 ± 0.05%ID/g in necrotic myocardium distribution values, normal myocardium is 0.09 ± 0.01% after English walnut naphtoquinone compounds 3h
The distributions ratios of ID/g, necrotic myocardium and normal myocardium are 8.00 times, there is good necrotic myocardium targeting ability.Blood distribution compared with
It is few, it is 0.38 ± 0.11%ID/g, but it is fast without naphthazarin compound.The number of possible hydroxyl can influence compound in blood plasma
Removing speed.
Table 2131Biodistribution data of the English walnut naphtoquinone compounds of I marks in model mouse body
| Tissue or organ | %ID/g ± SD |
| Blood | 0.38±0.11 |
| Thyroid gland | 0.21±0.01 |
| Lung | 0.23±0.02 |
| Spleen | 0.36±0.05 |
| Stomach | 0.17±0.01 |
| Small intestine | 0.17±0.06 |
| Large intestine | 0.18±0.02 |
| Kidney | 0.33±0.10 |
| Bladder | 0.27±0.19 |
| Bone | 0.10±0.04 |
| Liver | 0.34±0.08 |
| Brain | 0.01±0.00 |
| Survival myocardium | 0.09±0.01 |
| Necrotic myocardium | 0.72±0.05 |
| Necrotic myocardium/normal myocardium | 8.00 |
The TTC dyeing of the Rat of Myocardial Infarction model of embodiment 8 and the English walnut naphtoquinone compounds autoradiograph of iodine -131 mark
Contrast
Take isolated heart to 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
30min, imaged with phosphorus screen scanner scanning after end exposure.
Heart normal myocardium after 2%TTC is dyed shows as brick-red, and necrotic myocardium does not have coloring to be shown as white
Color, Fig. 3 can observe directly the necrotic myocardium region and normal myocardium region of heart.
The English walnut naphtoquinone compounds marked using the iodine -131 being prepared in embodiment 6 carry out autoradiograph, and Fig. 4 is shown
Distribution of the English walnut naphtoquinone compounds of the increased radioactivity of heart different zones, i.e. iodine -131 mark on heart, both contrast hair
The English walnut naphtoquinone compounds of existing iodine -131 mark can be optionally in myocardial infarction region clustering, almost no point of normal myocardium region
Cloth.
The preparation of 5- methoxyl groups -2-MNQ compound of the iodine -131 of embodiment 9 mark
1mg 5- methoxyl groups to be marked -2-MNQ compound (powdered) is weighed, is dissolved in 10mL
In DMSO, vibration shakes up, and obtains the solution that concentration is 0.1mg/mL.Take 400 μ L 0.1mg/mL 5- methoxyl group -2- methyl isophthalic acids, 4-
Naphthoquinone compound solution, which is added to, to be prepared in the painting pipe that Iodogen contents are 100 μ g, adds 100 μ L 2mCi Na131I is molten
Liquid and 20 μ L PBS solutions (pH=6.86), vibration shakes up, and is heated in water-bath (48 DEG C), reaction 2h or so, will be anti-
Liquid is answered to take out, terminating reaction.Mark rate is determined with TLC methods, Whatman filter paper is as carrier, and 0.1mol/L HCl are as flowing
Phase demodulation.
5- methoxyl groups -2-MNQ compound of the iodine -131 of embodiment 10 mark is in Rat of Myocardial Infarction
Distribution
The 5- methoxyl groups of the iodine -131 prepared in embodiment 9 mark -2-MNQ solution is added into PEG
400, propane diols (1: 1) dilution.Take myocardial infarction model rat 6, every intravenous injection iodine -131 mark 5- methoxyl group -2- first
The μ Ci (radiochemical purity 91%) of base -1,4-naphthoquinone solution 100.After 3h, euthanasia rat model, each internal organs (blood is taken
Liquid, thyroid gland, lung, spleen, stomach, small intestine, large intestine, kidney, bladder, bone, liver, brain, survival myocardium, necrotic myocardium etc.), weigh respectively
And radioactivity is measured with gamma counter, after decay correction, as a result it is expressed as the radioactive uptake of every gram of internal organs or tissue
Account for the percentage (%ID/g) of total injection dosage.
5- methoxyl groups-distribution results of the 2-MNQ compound in Rat of Myocardial Infarction of iodine -131 mark,
It is shown in Table 3.After 5- methoxyl groups -2-MNQ compound 3h of intravenous iodine -131 mark, it is in necrotic myocardium distribution values
0.45 ± 0.13%ID/g, normal myocardium are 0.07 ± 0.02%ID/g, and the distributions ratios of necrotic myocardium and normal myocardium are
6.43 times, necrotic myocardium can be targetted.Blood uptake values are higher, are 0.48 ± 0.13%ID/g, and blood is removed unhappy.Methoxyl group
And the significant effect that the introducing of methyl is accelerated not as hydroxyl to plasma clearance.Other liver sausage distribution is high compared with kidney, illustrates the chemical combination
Thing mainly passes through liver metabolism.
Table 31315- methoxyl groups-Biodistribution data of the 2-MNQ compound in model mouse body of I marks
| Tissue or organ | %ID/g ± SD |
| Blood | 0.48±0.13 |
| Thyroid gland | 0.25±0.03 |
| Lung | 0.35±0.12 |
| Spleen | 0.25±0.05 |
| Stomach | 0.30±0.21 |
| Small intestine | 0.23±0.06 |
| Large intestine | 0.24±0.15 |
| Kidney | 0.20±0.08 |
| Bladder | 0.15±0.03 |
| Bone | 0.03±0.00 |
| Liver | 0.31±0.17 |
| Brain | 0.02±0.00 |
| Survival myocardium | 0.07±0.02 |
| Necrotic myocardium | 0.45±0.13 |
| Necrotic myocardium/normal myocardium | 6.43 |
The preparation of the 1,4-naphthoquinone compound of the iodine -131 of embodiment 11 mark
1mg 1,4-naphthoquinone compounds (powdered) to be marked are weighed, are dissolved in 10mL DMSO, vibration shakes up, and obtains
Concentration is 0.1mg/mL solution.Take 400 μ L 0.1mg/mL 1,4-naphthoquinone solution to be added to prepare Iodogen contents and be
In 100 μ g painting pipe, 100 μ L 2mCi Na are added131I solution and 20 μ L PBS solutions (pH=7.40), vibration shakes up, and
Heat, reaction 20min or so, reaction solution is taken out, terminating reaction in water-bath (48 DEG C).Mark rate is determined with TLC methods,
Whatman filter paper is as carrier, and 0.1mol/L HCl are as flowing phase demodulation.
Distribution of the 1,4-naphthoquinone compound of the iodine -131 of embodiment 12 mark in Rat of Myocardial Infarction
The 1,4-naphthoquinone compound solution of the iodine -131 prepared in embodiment 11 mark is added into PEG 400, propane diols
(1: 1) dilute.Myocardial infarction model rat 6 is taken, the μ Ci of 1,4-naphthoquinone solution 100 of every intravenous injection iodine -131 mark (are put
Chemical purity is penetrated as 90%).After 3h, euthanasia rat model, take each internal organs (blood, thyroid gland, lung, spleen, stomach, small intestine, big
Intestines, kidney, bladder, bone, liver, brain, survival myocardium, necrotic myocardium etc.), weigh respectively and measure radiation with gamma counter and live
Property, after decay correction, 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)。
Distribution results of the 1,4-naphthoquinone compound of iodine -131 mark in Rat of Myocardial Infarction, are shown in Table 4.Intravenous iodine -131
It is 0.42 ± 0.15%ID/g in necrotic myocardium distribution values after the 1,4-naphthoquinone compound 3h of mark, normal myocardium 0.06
The distributions ratios of ± 0.03%ID/g, necrotic myocardium and normal myocardium are 7.00 times, there is certain necrotic myocardium targeting ability.But
Blood uptake values are higher, are 0.50 ± 0.08%ID/g.Liver sausage distribution is high compared with kidney, illustrates the compound mainly by liver generation
Thank.
Table 4131Biodistribution data of the 1,4-naphthoquinone compound of I marks in model mouse body
| Tissue or organ | %ID/g ± SD |
| Blood | 0.50±0.08 |
| Thyroid gland | 0.23±0.12 |
| Lung | 0.32±0.07 |
| Spleen | 0.23±0.12 |
| Stomach | 0.29±0.13 |
| Small intestine | 0.25±0.15 |
| Large intestine | 0.27±0.10 |
| Kidney | 0.23±0.17 |
| Bladder | 0.13±0.05 |
| Bone | 0.01±0.01 |
| Liver | 0.35±0.05 |
| Brain | 0.01±0.00 |
| Survival myocardium | 0.06±0.03 |
| Necrotic myocardium | 0.42±0.15 |
| Necrotic myocardium/normal myocardium | 7.00 |
It is prepared by the menadione compound of the iodine -131 of embodiment 13 mark
1mg menadione compounds (powdered) to be marked are weighed, are dissolved in 10mL DMSO, vibration shakes up, and obtains dense
Spend the solution for 0.1mg/mL.Take 400 μ L 0.1mg/mL menadione solution to be added to and prepare Iodogen contents as 100 μ g's
Tu Guanzhong, add 100 μ L 2mCi Na131I solution and 20 μ L PBS solutions (pH=6.86), vibration shakes up, and in water-bath
Heat, reaction 2h or so, reaction solution is taken out, terminating reaction in pot (48 DEG C).Mark rate, Whatman filter paper are determined with TLC methods
As carrier, 0.1mol/L HCl are as flowing phase demodulation.
Distribution of the menadione compound of the iodine -131 of embodiment 14 mark in Rat of Myocardial Infarction
The menadione solution of the iodine -131 prepared in embodiment 13 mark is added into PEG 400, propane diols (1: 1) is dilute
Release.Take myocardial infarction model rat 6, the μ Ci (radiochemically pures of menadione solution 100 of every intravenous injection iodine -131 mark
Spend for 92%).After 3h, euthanasia rat model, each internal organs (blood, thyroid gland, lung, spleen, stomach, small intestine, large intestine, kidney, wing are taken
Guang, bone, liver, brain, survival myocardium, necrotic myocardium etc.), weigh respectively and measure radioactivity with gamma counter, through decay
After correction, 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.
Distribution results of the menadione compound of iodine -131 mark in Rat of Myocardial Infarction, are shown in Table 5.Iodine -131 mark
It is 0.41 ± 0.17%ID/g in necrotic myocardium distribution values, normal myocardium is 0.05 ± 0.01% after menadione compound 3h
The distributions ratios of ID/g, necrotic myocardium and normal myocardium are 8.20 times, there is good necrotic myocardium targeting ability.But blood absorbs
It is worth slightly higher, is 0.42 ± 0.10%ID/g, the significant effect that the introducing of methyl is accelerated not as hydroxyl to plasma clearance.
Table 5131Biodistribution data of the menadione compound of I marks in model mouse body
| Tissue or organ | %ID/g ± SD |
| Blood | 0.42±0.10 |
| Thyroid gland | 0.21±0.01 |
| Lung | 0.38±0.15 |
| Spleen | 0.21±0.08 |
| Stomach | 0.25±0.12 |
| Small intestine | 0.24±0.07 |
| Large intestine | 0.26±0.03 |
| Kidney | 0.24±0.23 |
| Bladder | 0.17±0.08 |
| Bone | 0.02±0.00 |
| Liver | 0.33±0.13 |
| Brain | 0.01±0.00 |
| Survival myocardium | 0.05±0.01 |
| Necrotic myocardium | 0.41±0.17 |
| Necrotic myocardium/normal myocardium | 8.20 |
The preparation of the plumbagin compound of the iodine -131 of embodiment 15 mark
1mg plumbagin compounds (powdered) to be marked are weighed, are dissolved in 10mL DMSO, vibration shakes up, and obtains
Concentration is 0.1mg/mL solution.Take 400 μ L 0.1mg/mL plumbagin solution to be added to and prepare Iodogen contents as 100
In μ g painting pipe, 100 μ L 2mCi Na are added131I solution and 20 μ L PBS solutions (PH=6.86), vibration shakes up, and
Heat, reaction 1h or so, reaction solution is taken out, terminating reaction in water-bath (48 DEG C).Mark rate, Whatman are determined with TLC methods
Filter paper is as carrier, and 0.1mol/L HCl are as flowing phase demodulation.
Distribution of the plumbagin of the iodine -131 of embodiment 16 mark in Rat of Myocardial Infarction
The plumbagin solution of the iodine -131 prepared in embodiment 15 mark is added into PEG 400, propane diols (1: 1) is dilute
Release.Take myocardial infarction model rat 6, the μ Ci (radiochemistries of plumbagin solution 100 of every intravenous injection iodine -131 mark
93%) purity is.After 3h, euthanasia rat model, take each internal organs (blood, thyroid gland, lung, spleen, stomach, small intestine, large intestine, kidney,
Bladder, bone, liver, brain, survival myocardium, necrotic myocardium etc.), weigh respectively and measure radioactivity with gamma counter, through declining
After becoming correction, 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.
Distribution results of the plumbagin compound of iodine -131 mark in Rat of Myocardial Infarction, are shown in Table 6.Intravenous iodine -131
It is 0.52 ± 0.23%ID/g in necrotic myocardium distribution values after the plumbagin 3h of mark, normal myocardium is 0.06 ±
The distributions ratios of 0.01%ID/g, necrotic myocardium and normal myocardium are 8.67 times, there is good necrotic myocardium targeting ability, but blood
Liquid uptake values are higher, are 0.45 ± 0.15%ID/g, and blood is removed slower.Although the compound contains hydroxyl, do not show
Go out faster plasma clearance, it may be possible to receive the influence of methyl.Other liver sausage distribution is high compared with kidney, illustrates that the compound is main
Pass through liver metabolism.
Table 6131Biodistribution data of the plumbagin compound of I marks in model mouse body
| Tissue or organ | %ID/g ± SD |
| Blood | 0.45±0.15 |
| Thyroid gland | 0.19±0.13 |
| Lung | 0.32±0.18 |
| Spleen | 0.19±0.33 |
| Stomach | 0.27±0.15 |
| Small intestine | 0.22±0.03 |
| Large intestine | 0.25±0.12 |
| Kidney | 0.22±0.13 |
| Bladder | 0.16±0.07 |
| Bone | 0.02±0.01 |
| Liver | 0.31±0.04 |
| Brain | 0.02±0.00 |
| Survival myocardium | 0.06±0.01 |
| Necrotic myocardium | 0.52±0.23 |
| Necrotic myocardium/normal myocardium | 8.67 |
The preparation of 1, the 2- naphthoquinone compounds of the iodine -131 of embodiment 17 mark
1mg 1,2- naphthoquinone compounds (powdered) to be marked are weighed, are dissolved in 10mL DMSO, vibration shakes up, and obtains
Concentration is 0.1mg/mL solution.Take 400 μ L 0.1mg/mL 1,2- naphthoquinone solutions, which are added to, to be prepared Iodogen contents and be
In 100 μ g painting pipe, 100 μ L 2mCi Na are added131I solution and 20 μ L PBS solutions (PH=7.40), vibration shakes up, and
Heat, reaction 1h or so, reaction solution is taken out, terminating reaction in water-bath (48 DEG C).Mark rate is determined with TLC methods,
Whatman filter paper is as carrier, and 0.1mol/L HCl are as flowing phase demodulation.
Distribution of 1, the 2- naphthoquinones of the iodine -131 of embodiment 18 mark in Rat of Myocardial Infarction
1, the 2- naphthoquinone solutions of the iodine -131 prepared in embodiment 17 mark are added into PEG 400, propane diols (1: 1) is dilute
Release.Take myocardial infarction model rat 6, the μ Ci (radiochemistries of plumbagin solution 100 of every intravenous injection iodine -131 mark
91%) purity is.After 3h, euthanasia rat model, take each internal organs (blood, thyroid gland, lung, spleen, stomach, small intestine, large intestine, kidney,
Bladder, bone, liver, brain, survival myocardium, necrotic myocardium etc.), weigh respectively and measure radioactivity with gamma counter, through declining
After becoming correction, 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.
Distribution results of 1, the 2- naphthoquinone compounds of iodine -131 mark in Rat of Myocardial Infarction, are shown in Table 7.Intravenous iodine -131
Be 0.45 ± 0.16%ID/g in necrotic myocardium distribution values after 1, the 2- naphthoquinones 3h of mark, normal myocardium for 0.07 ±
The distributions ratios of 0.05%ID/g, necrotic myocardium and normal myocardium are 6.43 times, there is certain necrotic myocardium targeting ability.Simultaneously
Blood uptake values are higher, are 0.49 ± 0.09%ID/g.
Table 7131Biodistribution data of 1, the 2- naphthoquinone compounds of I marks in model mouse body
| Tissue or organ | %ID/g ± SD |
| Blood | 0.49±0.09 |
| Thyroid gland | 0.25±0.08 |
| Lung | 0.30±0.08 |
| Spleen | 0.25±0.10 |
| Stomach | 0.29±0.13 |
| Small intestine | 0.27±0.12 |
| Large intestine | 0.25±0.08 |
| Kidney | 0.27±0.15 |
| Bladder | 0.15±0.03 |
| Bone | 0.02±0.01 |
| Liver | 0.36±0.10 |
| Brain | 0.01±0.00 |
| Survival myocardium | 0.07±0.05 |
| Necrotic myocardium | 0.45±0.16 |
| Necrotic myocardium/normal myocardium | 6.43 |
The preparation of 4- amino -1,2- naphthoquinone compounds of the iodine -131 of embodiment 19 mark
1mg 4- amino -1,2- naphthoquinone compounds (powdered) to be marked are weighed, are dissolved in 10mL DMSO, are vibrated
Shake up, obtain the solution that concentration is 0.1mg/mL.Take 400 μ L 0.1mg/mL 4- amino -1,2- naphthoquinone solutions to be added to prepare
Iodogen contents are that 100 μ L 2mCi Na are added in 100 μ g painting pipe131I solution and 20 μ L PBS solutions (PH=
7.40), vibration shakes up, and is heated in water-bath (48 DEG C), reaction 1h or so, reaction solution is taken out, terminating reaction.Use TLC
Method determines mark rate, and Whatman filter paper is as carrier, and 0.1mol/L HCl are as flowing phase demodulation.
Distribution of 4- amino -1, the 2- naphthoquinones of the iodine -131 of embodiment 20 mark in Rat of Myocardial Infarction
4- amino -1,2- naphthoquinone solution of the iodine -131 prepared in embodiment 19 mark is added into PEG 400, propane diols
(1: 1) dilute.Take myocardial infarction model rat 6,4- amino -1,2- naphthoquinone solutions of every intravenous injection iodine -131 mark
100 μ Ci (radiochemical purity 90%).After 3h, euthanasia rat model, take each internal organs (blood, thyroid gland, lung, spleen,
Stomach, small intestine, large intestine, kidney, bladder, bone, liver, brain, survival myocardium, necrotic myocardium etc.), weigh and surveyed with gamma counter respectively
Radioactivity is measured, after decay correction, the radioactive uptake for being as a result expressed as every gram of internal organs or tissue accounts for the hundred of total injection dosage
Fraction (%ID/g).
Distribution results of 4- amino -1, the 2- naphthoquinone compounds of iodine -131 mark in Rat of Myocardial Infarction, are shown in Table 8.It is quiet
It is 0.48 ± 0.05%ID/g in necrotic myocardium distribution values after 4- amino -1, the 2- naphthoquinones 3h for noting iodine -131 mark, the normal heart
Flesh is 0.08 ± 0.02%ID/g, and the distributions ratios of necrotic myocardium and normal myocardium are 6.00 times, there is certain necrotic myocardium target
To ability.Blood uptake values are higher, are 0.51 ± 0.02%ID/g.Liver sausage distribution simultaneously is high compared with kidney, illustrates chemical combination owner
Will be by liver metabolism.
Table 8131Biodistribution data of 4- amino -1, the 2- naphthoquinone compound of I marks in model mouse body
| Tissue or organ | %ID/g ± SD |
| Blood | 0.51±0.02 |
| Thyroid gland | 0.22±0.04 |
| Lung | 0.21±0.09 |
| Spleen | 0.20±0.12 |
| Stomach | 0.32±0.13 |
| Small intestine | 0.33±0.09 |
| Large intestine | 0.35±0.04 |
| Kidney | 0.21±0.09 |
| Bladder | 0.13±0.02 |
| Bone | 0.03±0.01 |
| Liver | 0.46±0.20 |
| Brain | 0.02±0.01 |
| Survival myocardium | 0.08±0.02 |
| Necrotic myocardium | 0.48±0.05 |
| Necrotic myocardium/normal myocardium | 6.00 |
The preparation of chloro- 1, the 2- naphthoquinone compounds of 4- of the iodine -131 of embodiment 21 mark
Chloro- 1, the 2- naphthoquinone compounds (powdered) of 1mg 4- to be marked are weighed, are dissolved in 10mL DMSO, vibration is shaken
It is even, obtain the solution that concentration is 0.1mg/mL.400 chloro- 1, the 2- naphthoquinone compounds solution of μ L 0.1mg/mL 4- are taken to be added to preparation
Good Iodogen contents are that 100 μ L 2mCi Na are added in 100 μ g painting pipe131I solution and 20 μ L PBS solutions (PH=
7.40), vibration shakes up, and is heated in water-bath (48 DEG C), reaction 1h or so, reaction solution is taken out, terminating reaction.Use TLC
Method determines mark rate, and Whatman filter paper is as carrier, and 0.1mol/L HCl are as flowing phase demodulation.
Distribution of chloro- 1, the 2- naphthoquinone compounds of 4- of the iodine -131 of embodiment 22 mark in Rat of Myocardial Infarction
Chloro- 1, the 2- naphthoquinone compounds solution of 4- that the iodine -131 prepared in embodiment 21 is marked adds PEG 400, and third
Glycol (1: 1) dilutes.Take myocardial infarction model rat 6, chloro- 1, the 2- naphthoquinone solutions of 4- of every intravenous injection iodine -131 mark
100 μ Ci (radiochemical purity 90%).After 3h, euthanasia rat model, take each internal organs (blood, thyroid gland, lung, spleen,
Stomach, small intestine, large intestine, kidney, bladder, bone, liver, brain, survival myocardium, necrotic myocardium etc.), weigh and surveyed with gamma counter respectively
Radioactivity is measured, after decay correction, the radioactive uptake for being as a result expressed as every gram of internal organs or tissue accounts for the hundred of total injection dosage
Fraction (%ID/g).
Distribution results of chloro- 1, the 2- naphthoquinone compounds of 4- of iodine -131 mark in Rat of Myocardial Infarction, are shown in Table 9.Intravenous
It is 0.49 ± 0.13%ID/g in necrotic myocardium distribution values, normal myocardium is after chloro- 1, the 2- naphthoquinones 3h of 4- of iodine -131 mark
The distributions ratios of 0.08 ± 0.01%ID/g, necrotic myocardium and normal myocardium are 6.13 times, there is certain necrotic myocardium targeting energy
Power.Blood uptake values are still higher, are 0.50 ± 0.03%ID/g.Liver sausage distribution is high compared with kidney, illustrates that the compound is mainly led to
Cross liver metabolism.The introducing of chlorine influences little on compound blood Scavenging activity.
Table 9131Biodistribution data of chloro- 1, the 2- naphthoquinone compounds of 4- of I marks in model mouse body
| Tissue or organ | %ID/g ± SD |
| Blood | 0.50±0.03 |
| Thyroid gland | 0.21±0.03 |
| Lung | 0.23±0.04 |
| Spleen | 0.23±0.11 |
| Stomach | 0.31±0.12 |
| Small intestine | 0.34±0.15 |
| Large intestine | 0.37±0.03 |
| Kidney | 0.23±0.08 |
| Bladder | 0.12±0.01 |
| Bone | 0.02±0.01 |
| Liver | 0.45±0.13 |
| Brain | 0.01±0.01 |
| Survival myocardium | 0.08±0.01 |
| Necrotic myocardium | 0.49±0.13 |
| Necrotic myocardium/normal myocardium | 6.13 |
The preparation of 1, the 5- naphthoquinone compounds of the iodine -131 of embodiment 23 mark
1mg 1,5- naphthoquinone compounds (powdered) to be marked are weighed, are dissolved in 10mL DMSO, vibration shakes up, and obtains
Concentration is 0.1mg/mL solution.Take 400 μ L 0.1mg/mL 1,5- naphthoquinone compound solution, which is added to, to be prepared Iodogen and contain
Measure in the painting pipe for 100 μ g, add 100 μ L 2mCi Na131I solution and 20 μ L PBS solutions (PH=7.40), vibration is shaken
It is even, and heated in water-bath (48 DEG C), reaction 1h or so, reaction solution is taken out, terminating reaction.Mark rate is determined with TLC methods,
Whatman filter paper is as carrier, and 0.1mol/L HCl are as flowing phase demodulation.
Distribution of 1, the 5- naphthoquinone compounds of the iodine -131 of embodiment 24 mark in Rat of Myocardial Infarction
1, the 5- naphthoquinone compounds solution of the iodine -131 prepared in embodiment 23 mark is added into PEG 400, propane diols
(1: 1) dilute.Myocardial infarction model rat 6 is taken, the μ Ci of 1,5- naphthoquinone solutions 100 of every intravenous injection iodine -131 mark (are put
Chemical purity is penetrated as 93%).After 3h, euthanasia rat model, take each internal organs (blood, thyroid gland, lung, spleen, stomach, small intestine, big
Intestines, kidney, bladder, bone, liver, brain, survival myocardium, necrotic myocardium etc.), weigh respectively and measure radiation with gamma counter and live
Property, after decay correction, 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)。
Distribution results of 1, the 5- naphthoquinone compounds of iodine -131 mark in Rat of Myocardial Infarction, are shown in Table 10.Intravenous is iodo-
Be 0.43 ± 0.13%ID/g in necrotic myocardium distribution values after 1, the 5- naphthoquinones 3h of 131 marks, normal myocardium for 0.06 ±
The distributions ratios of 0.04%ID/g, necrotic myocardium and normal myocardium are 7.17 times, there is certain necrotic myocardium targeting ability.Blood
Uptake values are slightly higher, are 0.47 ± 0.05%ID/g.
Table 10131Biodistribution data of 1, the 5- naphthoquinone compounds of I marks in model mouse body
| Tissue or organ | %ID/g ± SD |
| Blood | 0.47±0.05 |
| Thyroid gland | 0.23±0.11 |
| Lung | 0.32±0.05 |
| Spleen | 0.27±0.08 |
| Stomach | 0.28±0.09 |
| Small intestine | 0.25±0.14 |
| Large intestine | 0.29±0.10 |
| Kidney | 0.26±0.13 |
| Bladder | 0.20±0.05 |
| Bone | 0.01±0.01 |
| Liver | 0.33±0.09 |
| Brain | 0.02±0.01 |
| Survival myocardium | 0.06±0.04 |
| Necrotic myocardium | 0.43±0.13 |
| Necrotic myocardium/normal myocardium | 7.17 |
The preparation of bromo- 1, the 5- naphthoquinone compounds of 4,8- diaminourea -2- of the iodine -131 of embodiment 25 mark
Bromo- 1, the 5- naphthoquinone compounds (powdered) of 1mg 4,8- diaminourea -2- to be marked are weighed, are dissolved in 10mL
In DMSO, vibration shakes up, and obtains the solution that concentration is 0.1mg/mL.Take 400 μ L 0.1mg/mL 4,8- diaminourea -2- bromo- 1,5-
Naphthoquinone compound solution, which is added to, to be prepared in the painting pipe that Iodogen contents are 100 μ g, adds 100 μ L 2mCi Na131I is molten
Liquid and 20 μ LPBS solution (PH=7.40), vibration shakes up, and is heated in water-bath (48 DEG C), reaction 1h or so, will react
Liquid takes out, terminating reaction.Mark rate is determined with TLC methods, Whatman filter paper is as carrier, and 0.1mol/L HCl are as mobile phase
Expansion.
Bromo- 1, the 5- naphthoquinone compounds of 4,8- diaminourea -2- of the iodine -131 of embodiment 26 mark are in Rat of Myocardial Infarction
Distribution
Bromo- 1, the 5- naphthoquinone compounds solution of 4,8- diaminourea -2- that the iodine -131 prepared in embodiment 25 marks is added
Enter PEG 400, propane diols (1: 1) dilution.Take myocardial infarction model rat 6, the 4,8- of every intravenous injection iodine -131 mark
The bromo- μ Ci (radiochemical purity 91%) of 1,5- naphthoquinone solutions 100 of diaminourea -2-.After 3h, euthanasia rat model, take each
Internal organs (blood, thyroid gland, lung, spleen, stomach, small intestine, large intestine, kidney, bladder, bone, liver, brain, survival myocardium, necrotic myocardium etc.),
Weigh respectively and measure radioactivity with gamma counter, after decay correction, be as a result expressed as putting for every gram of internal organs or tissue
Penetrating property absorbs the percentage (%ID/g) for accounting for total injection dosage.
Distribution results of bromo- 1, the 5- naphthoquinone compounds of 4,8- diaminourea -2- of iodine -131 mark in Rat of Myocardial Infarction,
It is shown in Table 11.It is 0.61 in necrotic myocardium distribution values after bromo- 1, the 5- naphthoquinones 3h of 4,8- diaminourea -2- of intravenous iodine -131 mark
± 0.11%ID/g, normal myocardium are 0.08 ± 0.04%ID/g, and the distributions ratios of necrotic myocardium and normal myocardium are 7.63 times,
There is good necrotic myocardium targeting ability.It is 0.52 ± 0.04%ID/g but blood uptake values are higher.Liver sausage distribution is higher, says
The bright compound mainly passes through liver metabolism.It is higher consistent with the distribution of 4- amino -1,2- naphthoquinones liver sausage, illustrate that the introducing of amino can
Distribution of the compound in liver can be added, but does not promote its removing in blood plasma.
Table 11131Biodistribution data of bromo- 1, the 5- naphthoquinone compounds of 4,8- diaminourea -2- of I marks in model mouse body
| Tissue or organ | %ID/g ± SD |
| Blood | 0.52±0.04 |
| Thyroid gland | 0.25±0.06 |
| Lung | 0.30±0.03 |
| Spleen | 0.25±0.12 |
| Stomach | 0.29±0.10 |
| Small intestine | 0.30±0.13 |
| Large intestine | 0.32±0.11 |
| Kidney | 0.22±0.07 |
| Bladder | 0.17±0.04 |
| Bone | 0.02±0.00 |
| Liver | 0.57±0.32 |
| Brain | 0.01±0.00 |
| Survival myocardium | 0.08±0.04 |
| Necrotic myocardium | 0.61±0.11 |
| Necrotic myocardium/normal myocardium | 7.63 |
The preparation of bromo- 1, the 5- naphthoquinone compounds of 4,8- diaminourea -2,6- bis- of the iodine -131 of embodiment 27 mark
Bromo- 1, the 5- naphthoquinone compounds (powdered) of 1mg 4,8- diaminourea -2,6- bis- to be marked are weighed, are dissolved in
In 10mL DMSO, vibration shakes up, and obtains the solution that concentration is 0.1mg/mL.Take 400 μ L 0.1mg/mL4,8- diaminourea -2,6- bis-
Bromo- 1,5- naphthoquinone compounds solution, which is added to, to be prepared in the painting pipe that Iodogen contents are 100 μ g, adds 100 μ L 2mCi
Na131I solution and 20 μ L PBS solutions (PH=7.40), vibration shakes up, and is heated in water-bath (48 DEG C), and reaction 1h is left
The right side, reaction solution is taken out, terminating reaction.Mark rate is determined with TLC methods, Whatman filter paper is made as carrier, 0.1mol/L HCl
To flow phase demodulation.
Bromo- 1, the 5- naphthoquinone compounds of 4,8- diaminourea -2,6- bis- of the iodine -131 of embodiment 28 mark are in Rat of Myocardial Infarction
On distribution
Bromo- 1, the 5- naphthoquinone compounds of 4,8- diaminourea -2,6- bis- that the iodine -131 prepared in embodiment 27 is marked are molten
Liquid adds PEG 400, propane diols (1: 1) dilution.Myocardial infarction model rat 6 is taken, what every intravenous injection iodine -131 marked
The bromo- μ Ci (radiochemical purity 93%) of 1,5- naphthoquinone solutions 100 of 4,8- diaminourea -2-.After 3h, euthanasia rat model,
Take each internal organs (blood, thyroid gland, lung, spleen, stomach, small intestine, large intestine, kidney, bladder, bone, liver, brain, survival myocardium, necrotic myocardium
Deng), weigh respectively and measure radioactivity with gamma counter, after decay correction, be as a result expressed as every gram of internal organs or tissue
Radioactive uptake account for the percentage (%ID/g) of total injection dosage.
Distribution of bromo- 1, the 5- naphthoquinone compounds of 4,8- diaminourea -2,6- bis- of iodine -131 mark in Rat of Myocardial Infarction
As a result, 12 are shown in Table.After bromo- 1, the 5- naphthoquinones 3h of 4,8- diaminourea -2,6- bis- of intravenous iodine -131 mark, in necrotic myocardium distribution number
It is 0.10 ± 0.03%ID/g, necrotic myocardium and normal myocardium distributions ratios to be worth for 0.65 ± 0.23%ID/g, normal myocardium
For 6.50 times, there is certain necrotic myocardium targeting ability.Blood uptake values are higher, are 0.56 ± 0.05%ID/g.Liver sausage is distributed
It is high compared with kidney, illustrate that the compound mainly passes through liver metabolism.Compared to bromo- 1, the 5- naphthoquinone compounds of 4,8- diaminourea -2-, bromine
Number removing of the compound in blood plasma is influenceed it is little.
Table 12131Bio distribution of bromo- 1, the 5- naphthoquinone compounds of 4,8- diaminourea -2,6- bis- of I marks in model mouse body
Data
| Tissue or organ | %ID/g ± SD |
| Blood | 0.56±0.05 |
| Thyroid gland | 0.26±0.10 |
| Lung | 0.29±0.05 |
| Spleen | 0.26±0.09 |
| Stomach | 0.33±0.14 |
| Small intestine | 0.31±0.05 |
| Large intestine | 0.35±0.07 |
| Kidney | 0.20±0.04 |
| Bladder | 0.16±0.03 |
| Bone | 0.01±0.00 |
| Liver | 0.63±0.25 |
| Brain | 0.02±0.01 |
| Survival myocardium | 0.10±0.03 |
| Necrotic myocardium | 0.65±0.23 |
| Necrotic myocardium/normal myocardium | 6.50 |
In the way of in embodiment 1 to 28, respectively to technetium -99m, ytterbium -111, ytterbium -113m, iodo- 123, iodo- 124, iodine
125th, the naphthoquinone compound of Value linear, gallium-68, copper -64 and Rubidium-86 mark carries out targeting focusing experiment, it is found that it has
With targeting essentially identical in embodiment.Therefore, it can be equally used for preparing the developer of necrotic myocardium imaging.
Claims (6)
1. application of the naphthoquinone compound of labelled with radioisotope in necrotic myocardium imagewise development agent is prepared.
2. application according to claim 1, it is characterized in that the naphthoquinone compound is compound shown in formula I or its medicine
Acceptable salt on,
Wherein, R1、R2It is selected from independently and arbitrarily：-H、-OH、-OCH3、-OC2H5、-NH2、-COOH、-COOCH3、-COOC2H5、-
CH3,-Cl ,-Br ,-CN, and R1、R2To be monosubstituted or disubstituted.
3. application according to claim 1, it is characterized in that the naphthoquinone compound be the shown compounds of formula I ' or its
Pharmaceutically acceptable salt,
Wherein, R1、R2It is selected from independently and arbitrarily：-H、-OH、-OCH3、-OC2H5、-NH2、-COOH、-COOCH3、-COOC2H5、-
CH3,-Cl ,-Br ,-CN, and R1、R2To be monosubstituted or disubstituted.
4. according to the application described in claim 1, it is characterized in that the naphthoquinone compound be compound shown in formula I " or
Its pharmaceutically acceptable salt,
Wherein, R1、R2It is selected from independently and arbitrarily：-H、-OH、-OCH3、-OC2H5、-NH2、-COOH、-COOCH3、-COOC2H5、-
CH3,-Cl ,-Br ,-CN, and R1、R2To be monosubstituted or disubstituted.
5. according to claim 1 appoint described in application, it is characterized in that the naphthoquinone compound refers to there is following structure
Compound,
6. according to the application described in claim 1, it is characterized in that：The radio isotope is iodo- 123, iodo- 124, iodo-
125th, iodine -131, technetium -99m, ytterbium -111, ytterbium -113m, Value linear, gallium-68, copper -64, Rubidium-86.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108743981A (en) * | 2018-06-22 | 2018-11-06 | 中国药科大学 | Application of the serotonin and 5HTP of labelled with radioisotope in necrotic myocardium imaging |
| CN112079898A (en) * | 2019-06-12 | 2020-12-15 | 韩国原子力研究院 | Method for labeling radioactive element using quinone compound, radiolabeled compound, and radioactive element labeling kit |
| CN113769121A (en) * | 2020-09-18 | 2021-12-10 | 中国原子能科学研究院 | Radiotherapeutic medicine for diseases caused by coronavirus or influenza virus and preparation method thereof |
-
2016
- 2016-09-30 CN CN201610878130.4A patent/CN107875405A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108743981A (en) * | 2018-06-22 | 2018-11-06 | 中国药科大学 | Application of the serotonin and 5HTP of labelled with radioisotope in necrotic myocardium imaging |
| CN112079898A (en) * | 2019-06-12 | 2020-12-15 | 韩国原子力研究院 | Method for labeling radioactive element using quinone compound, radiolabeled compound, and radioactive element labeling kit |
| CN113769121A (en) * | 2020-09-18 | 2021-12-10 | 中国原子能科学研究院 | Radiotherapeutic medicine for diseases caused by coronavirus or influenza virus and preparation method thereof |
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