CN1169580C - 166 Ho-DTPA, its preparing method and application as liquid radiation source - Google Patents
166 Ho-DTPA, its preparing method and application as liquid radiation source Download PDFInfo
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- CN1169580C CN1169580C CNB001072471A CN00107247A CN1169580C CN 1169580 C CN1169580 C CN 1169580C CN B001072471 A CNB001072471 A CN B001072471A CN 00107247 A CN00107247 A CN 00107247A CN 1169580 C CN1169580 C CN 1169580C
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Abstract
<166>Ho-diethylenetriamine pentaacetic acid(DTPA)can be used as a liquid radiation source for the prevention of restenosis in angiostenosis disease after the blood vessel shaping operation, and has the advantage of keeping stable form for a long time and being excreted rapidly when the<166>Ho-DTPA is excreted in vivo. A method for preparing<166>Ho-DTPA is also provided.
Description
Technical field
The present invention relates to
166Diethylene-triamine pentaacetic acid of Ho labelling (DTPA) and its preparation method.More particularly, the present invention relates to
166Ho-DTPA, it is used as liquid radiation sources, is used to prevent the generation of the angioplasty operation back restenosis of angiostenosis disease, and it has keeps stable form for a long time and works as
166The advantage that Ho-DTPA can be excreted rapidly during seepage in vivo.
Background technology
When the accumulation owing to cholesterol, insoluble calcium etc. causes blood vessel to narrow down, cause angiostenosis disease (being a kind of coronary artery disease) usually.When coronary artery narrowed down owing to arteriosclerosis, the mobile quilt of blood hindered, and oxygen and nutrient can not be provided, and will cause myocardial necrosis like this, causes myocardial infarction and angina pectoris.
The coronary stricture disease is mainly used percutaneous through tube chamber coronary angioplasty (PTCA) treatment, wherein inserts balloon catheter blood vessel is broadened.Since Gruentzig underwent surgery to the people for the first time in 1977, PTCA is extensive use.Surpass 500,000 people according to reports at present from PTCA benefited (Holmes, D.R. etc., American Journal of Cardiology (Am.J.Cardiol.), 53:77C-81C, 1984).Angioplasty shows that the clinical success rate is approximately 95%.
Yet the subject matter of using the PTCA treatment is restenosis.In using the angioplasty of balloon catheter or afterwards, acute closed or restenosis can take place.30-45% accepts this patients with surgical restenosis can occur in angioplasty was performed the operation back six months according to reports.
The mechanism that produces restenosis after performing the operation through the tube chamber coronary angioplasty can be interpreted as the refigure of blood vessel, the propagation of smooth muscle cell (SMC) and the formation of extracellular matrix (Withers, H.R. etc., cancer (Cancer) 34:39-47,1974 usually; Thames, H.D. etc., Int.J.Radiat.Onco.Biol., Phys., 7:1591-1597,1981).Usually SMC can not carry out the competent cell division in the blood vessel, but when blood vessel by physical injury or when being upset, SMC transfer intravasation inner membrance is bred formative tissue substrate.
Therefore, restenosis prevents with that narrow blood vessel is broadened is the same important.In order to prevent restenosis, carried out a lot of effort, comprise administration such as antithrombotic drug, anticoagulant, steroid drugs, calcium channel blocker, cholchicine and gene therapy.Yet, can not obtain enough effects that prevents by the administration of these medicines.Because medicine flows in blood vessel, be difficult in required internal blood vessel position and keep lasting drug effect.Therefore, unlike oncotherapy, administration is not obvious to blood vessel inner cell inhibited proliferation.
Also known other method that prevents restenosis comprises atherosis speckle excision, uses through tube chamber and extract conduit (TEN), excitation laser coronary angioplasty and expansion implantation.Especially, latest developments a kind of angioplasty of application of radiation, wherein the cell around the desired area is because radiation causes necrosis, with the propagation of basic inhibition SMC.
The radioactive nucleus that is used for radiation treatment is for can launch α β ray or the gamma-ray radioactive nucleus of α.Launching Beta-ray radioactive nucleus comprises
32P, Sr,
90Y,
109Pd,
131I,
153Sm,
165Dy,
166Ho,
169Er,
188Re,
198Au and
99mTc.Launching gamma-ray radioactive nucleus is
192Ir,
57Co,
60Co,
48V and
125I.In them, have the radiosiotope of high β ray energy, as
188Re and
166Ho is used for angioplasty.
188Re can from
188W/
188The Re generator obtains at an easy rate, but it need a neutron flow be 10
15N/cm
2Second or higher atomic reactor and high preparation cost.On the contrary,
166Ho has superiority aspect preparation cost, because it can be 10 at the neutron flow
14N/cm
2Be produced in a large number in the small research reactor of second.
The present inventor has been developed a kind of application
166Ho (NO
3)
3As the balloon catheter of liquid radiation sources, be applied to the patient of angioplasty, these patients still still suffer narrow misery because coronary stricture carried out a balloon angioplasty at least or expanded implant surgery.Use
166Ho (NO
3)
3Surgical presentation as liquid radiation sources
166Ho can highly prevent the generation of restenosis.
Yet at intra-operative, the balloon rupture of conduit leaks out radionuclide, and radionuclide can stop a very long time in vivo, is absorbed by bone marrow or other organ, can produce fatal influence to health like this.In carrying out radiation treatment, guarantee that the safety of radioactive substance is extremely important.When the radioactive substance leakage enters in the body, if possible, should in body, excrete out rapidly.
66Ho (NO
3)
3It is unfavorable in this respect because it flushes out very slow in the body (accumulating in major organs because of it, in kidney, spleen and skeleton).
Because
99mThe diethylene-triamine pentaacetic acid of Tc labelling (DTPA) is accumulated by kidney or bladder in vivo and is drained, so it is widely used in the diagnosis of renal function.(Majali M.A.,J.Radianal.Nucl.Chem.,170,471)。This advantage of DTPA can be used for detecting
188The DTPA of Re labelling distribution (LeeJ. etc., Kor.J.Nucl.Med., 1997,31,427) in vivo.
As mentioned above, still
188It is 10 that the preparation of Re needs a neutron flow
15N/cm
2Second or higher atomic reactor, so preparation cost height.In addition and human serum mix, show
188The labeling effciency of Re-DTPA reduced to 88% or lower after 1 hour.In other words, safety is bad in vivo for this chemical compound.
In order to overcome the shortcoming of top describing method, the present inventor has carried out deeply and comprehensively research radiocurable angioplasty, and is unremitting, found finally a kind ofly to be used for radiocurable liquid radiation sources, and developed
166The DTPA of Ho labelling.
166Ho-DTPA can highly prevent restenosis, and because it can be drained in body rapidly, it is safe to health.
Summary of the invention
An object of the present invention is to provide
166Ho-DTPA is used for radiotherapy as liquid radiation sources.
Another object of the present invention provides a kind of preparation
166The method of Ho-DTPA.
Based on the present invention, provide
166Ho-DTPA, it is used to prevent the angioplasty operation generation of restenosis afterwards of angiostenosis disease as liquid radiation sources.
A kind of preparation also is provided
166The method of Ho-DTPA, wherein DTPA and Ho (NO
3)
3, HoCl
3Or their hydrate Ho (
166Ho+
165Ho) and the DTPA molar ratio range under the condition between 1: 1 to 1: 8, react.
Description of drawings
From detailed description below in conjunction with accompanying drawing, will more be expressly understood the present invention above-mentioned with other purpose, feature and other superiority, wherein:
Fig. 1 is a sketch map, illustrates usefulness
166The balloon catheter that Ho-DTPA fills;
Fig. 2 a is
166Ho (NO
3)
3Liquid chromatogram;
Fig. 2 b is
166The liquid chromatogram of Ho-DTPA;
Fig. 3 illustrates usefulness
166The photo of the rabbit of Ho-DTPA injection, it is to take in chronological order with gammacamera; With
Fig. 4 illustrates and is using
166Detected radioactivity energy is with respect to the variation of time in the right side of the rabbit of Ho-DTPA injection and the left kidney.
The description of major part among the figure:
1: balloon catheter
2: use
166The air bag that Ho-DTPA fills
3: the coronary blood tube wall
4: narrow
166Ho is a kind of radioelement, and its half-life is 26.8 hours, and maximum β ray energy is 1.86MeV.This radiosiotope is supposed to show good radiotherapy effect, because energy of a little less than its emission and high β ray energy.And that tradition is used for is radiocurable
188The preparation of Re needs expensive
188W/
188The Re generator,
166Ho can prepare in a large number with the small test reactor.
166Another advantage of Ho is the interior location that it can be used to observe health, is similar to because it can also be launched
99mThe gamma-rays of Tc, it can be used as visible nucleic.
In vivo, known DTPA transfers to kidney or bladder.For example,
99mTc-DTPA is widely used in the diagnosis of kidney, especially for the diagnosis of glomerular filtration function.
Therefore, according to one embodiment of the invention, provide a kind of
166The DTPA of Ho labelling (hereinafter referred to as "
166Ho-DTPA "), it is used for radiotherapy as liquid radiation sources, combines
166The advantage of Ho and DTPA.
According to the present invention
166Ho and DTPA in conjunction with the time, obtain
166Can there be 24 hours in the Ho-DTPA complex or the longer time under neutrallty condition (pH7) and different acid condition, and keeps stable.Therefore, even it exposes in vivo, because
166Ho can guarantee the application security of liquid radiation sources securely by the DTPA labelling.In addition, when
166Ho-DTPA directly leaks in vivo, and it moves to kidney or bladder at short notice, is difficult in other organ accumulation, thereby can passes through homaluria.Therefore,
166Ho-DTPA can be enhanced as the safety of radiation source.
166Ho emission β ray and gamma-rays mainly are the β rays, and this nucleic can be used to treat local lesion like this, and does not destroy contiguous normal structure.From
166The Ho radiation emitted can make the SMC necrosis of blood vessel, and a kind of method that solves vascular restenosis is provided in the angioplasty process usually.Therefore, combine physiology's superiority of DTPA,
166The radiotherapy effect of Ho allows
166Ho-DTPA is used to prevent the postoperative restenosis of angioplasty as a kind of safe liquid radiation sources, uses balloon catheter as PTCA, is used for the angiostenosis disease, comprises arteriosclerotic treatment.
When balloon catheter was used for the treatment of the coronary stricture disease, mensuration was suitable for preventing that the radiation source of coronary restenosis is extremely important.The relevant experimental data of radiation absorbed dose shows, when the time restriction of treatment phase during at 150 seconds, balloon catheter preferably contains of the present invention
166The initial dose of Ho-DTPA is 20-100mCi (according to the treatment amount of radiation of about 20Gy).
166Ho-DTPA be except being produced as the liquid radiation sources of balloon catheter at an easy rate, the not size of tube airbag and shape, and it can be filled the air bag of packing into.Therefore, in the time of in being inclusive in air bag, liquid of the present invention
166Ho-DTPA only shines needs radiating position, and the discord blood vessel directly contacts.This balloon catheter can be bought with commonsense method preparation and commerce.About Fig. 1, it illustrate contain of the present invention
166Ho-DTPA is as the example of the balloon catheter of liquid radiation sources.
According to another embodiment of the invention, it provides a kind of preparation that is used for
166The method of Ho-DTPA.DTPA and Ho (NO
3)
3, HoCl
3Or their hydrate reaction preparation
166Ho-DTPA.For reaction, Ho (
166Ho+
165Ho) and DTPA mol ratio preferable range between 1: 1 to 1: 8, more preferably from 1: 3 to 1: 6.This labeled reactant preferably maintains under neutrality or the acid condition, and promptly pH is 7 or lower.
In the method for the invention,
166Ho is approximately 100% to the productive rate that DTPA carries out labelling.
The specific embodiment
The present invention may be better understood according to the following examples, proposes these embodiment and be for the present invention is described, and can not be interpreted as restriction the present invention.
166The preparation 1 of Ho-DTPA
8.1mg
165Ho (NO
3)
35H
2O obtains by neutron exposure
166Ho (NO
3)
35H
2O.In order to obtain DTPA: Ho (
165Ho+
166Ho) mol ratio is 3.98: 1 a compositions, with 0.1mlHo (NO
3)
35H
2The 2ml HCl of O (pH is 3) solution be added to 12mg DTPA (in calcium trisodium salt hydrate, aldrich) in, add to 1.1ml with normal saline buffer solution then.The solution pH value scope that obtains is at 5.0-5.5, effectively Ho (NO
3)
35H
2The radioactivity energy of O is 1.3mCi.
Response composite carries out chromatography, and its immobile phase is a freshly prepd thin layer chromatography silicic acid (ITLC-SA), and mobile phase is 75% methanol aqueous solution, measures labelling productive rate (EG﹠amp with the ITLC scanner then; G Berthold linear Analyzer).Scan-data shows that DTPA almost completely is marked as
166Ho-DTPA.Free type
166Ho (NO
3)
3With
165Ho (NO
3)
3Separated, Rf value is respectively 0-0.2, and (Fig. 2 a) and 0.9-1.0 (Fig. 2 b).
166The preparation 2 of Ho-DTPA
5mg's
165Ho
2O
3Obtain by neutron exposure
166Ho
2O
3, then it is dissolved among the 2NHCl.DTPA is added in this solution, obtain mol ratio and be 3.98: 1 DTPA: Ho (
165Ho+
166Ho).With rare NaOH the solution pH value that obtains is adjusted to 5.0-5.5, obtains
166Ho-DTPA.With recording the labelling productive rate with embodiment 1 identical method is 99.9%.
Experimental example 1
Contain
166The impurity analysis of the nucleic of Ho
To ' Hanaro ' research reactor made
166Ho carries out impurity analysis.In this, adopt the Ge detector (EG﹠amp that uses high energy resolution; G, gamma-rays spectroscope Ortec).Analysis result is as shown in table 1.
Table 1
Nucleic | Half-life | Radioactivity energy (Bp) | Impurity 166Ho(10 -6) |
166Ho | 26.8 hour | 573,200 | - |
166mHo | 1200 | 1,858 | 0.564 |
177mLu | 160.9 my god | 1,550 | 0.5 |
177Lu | 6.71 my god | 8.390 | 10.79 |
141Ce | 32.5 my god | 457 | 0.19 |
169YB | 32.02 my god | 2,488 | 1.02 |
175Yb | 4.19 my god | 17.640 | 54.15 |
140La | 40.22 hour | 90 | 8.91 |
As shown in table 1, find to prepare with Hanaro
166The radioimpurity radioactive impurity that Ho produces and
166Ho compares, and radioactivity is very little, therefore can not influence the mensuration of radiation absorbed dose.
Experimental example 2
166Ho-DTPA is according to the stability of passage of time
Detected with the following method
166The stability of Ho-DTPA and time relation.To lyophilization, each contains the 1ml Ho (NO that adds 108mCi and 202mCi in one group of bottle of 12mg DTPA respectively
3)
35H
2O (pH is 3), the pH value of the acetate buffer regulator solution by adding 0.2ml is to 6.0-6.3 subsequently.After 30 minutes, 2 hours, 3 hours, 6 hours and 24 hours, be that ITLC-SA, mobile phase are the chromatograph of 75% methanol aqueous solution by immobile phase with reactant.Right by the ITLC scanner then
166The amount of radiation of Ho-DTPA is measured, and the result who obtains is as shown in table 2 below.
Table 2
Time (hrs) | Radiochemical impurity (%) a | |
166Ho-DTPA(108mCi) | 166Ho-DTPA(202mCi) | |
0.5 | 99% | 99% |
2 | 98% | 98% |
3 | 98% | 98% |
6 | 98% | 79.8% |
24 | 98% | 70% |
A 166The radioactivity energy of Ho-DTPA depends on
166The radioactivity energy of Ho integral body
For 108mCi, radiolabeled DTPA behind labelling 24 hours still stable, record it and keep the labelling productive rate 98% or higher.For 202mCi,
166Ho-DTPA kept the labelling productive rate 98% or higher in 3 hours behind labelling, 24 hour-symbols productive rates are approximately 70% behind the labelling.
Do not separate from DTPA
166Ho,
166Ho-DTPA can keep its integrity in a very long time.Therefore, even work as
166Ho-DTPA leaks when entering in the body, and complex also moves to kidney or bladder according to the character of DTPA, is difficult to enter other organ.Therefore, prove below
166Ho-DTPA is very stable and safety.
Experimental example 3
166The stability that Ho-DTPA changes pH value
Detected with the following method
166The stability that Ho-DTPA changes pH value.To lyophilization, each contains the 0.1mlHo (NO that adds 55mCi in one group of bottle of 12mg DTPA respectively
3)
35H
2O (pH is 3) adds the normal saline buffer solution of 0.9ml then, subsequently by adding the pH value to 1.67 of not commensurability acetate buffer regulator solution, 3.1,5.05 and 6.81.After 30 minutes, be that ITLC-SA, mobile phase are the chromatograph of 75% methanol aqueous solution by immobile phase with reactant.Right by the ITLC scanner then
166The amount of radiation of Ho-DTPA is measured, and the result who obtains is as shown in table 3 below.
Table 3
pH | Labelling productive rate (%) |
1.67 | 99% or more |
3.1 | 99% or more |
5.05 | 99% or more |
6.81 | 99% or more |
It is as shown in table 3,
166Ho-DTPA is highly stable under neutrality or acid condition.
Experimental example 4
166Ho-DTPA is Determination of distribution in the mice body
To the male Sprague-Dawley of 8 average weight 257 ± 7.1g (SD) mice, be 200 ± 20 μ Ci's by the tail vein injected dose
166Ho-DTPA.After the intravenous injection 15 minutes and 90 minutes, respectively 4 mices are used the ether deep anaesthesia, dissect.After dissecting mice excision major organs (liver, spleen, kidney, bladder, testis, lung, heart, brain), muscle, fat and skeleton, weigh, with flasher (Canberra) the calculating radioactivity of suitable model.Calculate the accumulation exit dose of each organ and tissue according to whole injected dose, and obtain every gram injected dose percentage rate of each organ and tissue with it.The result is as shown in table 4 below
Table 4
Organ or tissue | Every gram injected dose percentage rate (%ID/g) a | |
After 15 minutes | After 90 minutes | |
Blood | 2.20 0.269 | 2.22 0.038 |
Liver | 5.09 0.719 | 1.46 0.199 |
Bladder | 54.71 20.929 | 1.26 0.355 |
Liver | 0.77 0.048 | 0.25 0.081 |
Muscle | 0.46 0.067 | 0.02 0.010 |
Fat | 0.44 0.062 | 0.04 0.037 |
Skeleton | 0.58 0.087 | 0.05 0.015 |
Spleen | 0.84 0.087 | 0.48 0.128 |
Heart | 0.78 0.107 | 0.07 0.006 |
Lung | 1.28 0.167 | 0.15 0.040 |
Testis | 0.39 0.029 | 0.06 0.006 |
Brain | 0.06 0.004 | 0.01 0.001 |
aMean standard deviation
As shown in table 4, after the intravenous injection 15 minutes, detect bladder radioactive values the highest (54.7%ID/g), the kidney radioactive values is (5.09%ID/g) secondly, is higher than blood (2.20%ID/g).Therefore, from data as can be known, the great majority injection
166Ho-DTPA transfers to kidney and bladder.After the intravenous injection 90 minutes, be respectively 1.46 and 1.26%ID/g in kidney and the detected radioactivity of bladder.Integrate, data show what great majority were injected
166Ho-DTPA transfers to kidney and bladder, drains in body in a short period of time.In addition, compare, find that the uptake ratio of other organ and tissue radiation material is very low with blood.
Experimental example 5
166Ho-DTPA is Determination of distribution in the rabbit body
Giving three male rabbit (New Zealand's whites, (dosage is 6mg/kg to average weight 2731 ± 52.9g) by intramuscular injection ketamine (dosage is 25mg/kg, Yuhan company, Korea S) and Rumpoon, Korea S's Baeyer) after the anesthesia, be 2.0 ± 0.2mCi's by the ear vein injected dose respectively
166Ho-DTPA.Afterwards, the picture of the whole health of usefulness gamma camera (Diacam, Siemens, Germany) shooting rabbit 30 minutes is with the behavior after the injection of monitoring medicine.In this, photographing unit is furnished with parallel pin hole pointing instrumentation, and the adjusting energy value is 80keV, 20% of window width.By utilizing the pointing instrumentation media, obtain image, the result is as shown in Figure 3.Right kidney and left kidney desired area from adding figure obtain time-acttivity curve, and appliance computer system (ICON) obtains maximum distribution time (T about kidney according to it then
Max) and half-life (T
1/2), as shown in Figure 4.
Referring to Fig. 3, the great majority injection
166Ho-DTPA in back 30 minutes of injection by kidney and bladder drainage.
Proved injection by time-activity curve
166The rapid drainage of Ho-DTPA.Observe radioactivity kidney significantly at the activity value that is similar to background of injection minimizing in back 30 minutes from Fig. 4.Detected T in left kidney
MaxAnd T
1/2Be respectively detected T in right kidney 4 minutes and 22 minutes
MaxAnd T
1/2Be respectively 4 minutes and 19 minutes.Therefore, think what great majority were injected
166Ho-DTPA in back 30 minutes of injection by kidney and bladder drainage.
Experimental example 6
The mensuration of the suitable absorption dosage of treatment
166Ho is used as the radiation source of balloon catheter to prevent coronary restenosis, has measured it by the following method and has been suitable for radiocurable initial radioactive intensity.
Use the EGS4 coding system, calculated
166The β that Ho launches in water and the distribution of gamma-ray radiation absorbed dose.In this experiment, be under the situation of 20Gy in the suitable amount of radiation of supposition treatment, obtain the initial radioactive intensity of radiation source.It is that 20mm, diameter are the cylinder of 3mm that radioactive source is considered to length.Because be that a line is present in the air bag, the pipe that 20mm is long, diameter is 1mm is placed in the radioactive source.Suppose that radioactive source is to distribute equably to pass through cylinder.10 grid are arranged radially, and well-regulated interval 0.5mm is the center with the radiation source, and the human body radiation absorbed dose percentage rate for about every injected dose of each little lattice calculates object.
By using the EGS4 coding system, as measurement to liquid water,
166In the object of the radial distribution of surface distance 0.5mm of Ho cylinder sample, find that β and gamma-ray radiation absorbed dose are respectively every GBq of 10.87cGy/s and the every GBq of 0.29cGy/s.Therefore, according to the experimental result that obtains, calculating the suitable initial radiation dosage of radiotherapy is 32.31mCi (in 150 seconds treatment times, treating amount of radiation altogether is 20Gy).In addition, when initial radiation dosage was represented as radioactivity bulk density 100mCi/mL, in the object of 0.5mm (error is 1.66%), calculating its radiation absorbed dose was 0.0519cGy/s in the radial sample surfaces distance that is distributed in.
As previously mentioned, because
166Ho-DTPA mainly launches the β ray, and it can be used for the treatment of local damage, and does not damage contiguous normal skin, and because
166Ho-DTPA is liquid, and it can be processed at an easy rate, and do not need special instrument.In addition, when
166When Ho-DTPA leaked in vivo, it can be drained rapidly by kidney, prevented that radioactive substance from being absorbed by normal structure.And the radiological performance quantitative determination shows and works as in the urine
166When Ho-DTPA leaks in vivo, injection
166The leakage of Ho-DTPA can promptly be transferred in the urine by necessity.Therefore, of the present invention
166Ho-DTPA is used to prevent the postoperative restenosis of angioplasty as a kind of safe liquid radiation sources, uses balloon catheter as PTCA, is used for the angiostenosis disease, comprises arteriosclerotic treatment.
The present invention adopts illustrational method to be described, and should think that the term that uses is for feature description, rather than restriction.According to top technology, the present invention may carry out many modifications and change.Therefore, should think in the scope of accompanying Claim that the present invention can implement being different under the specifically described condition.
Claims (5)
1.
166The diethylene-triamine pentaacetic acid of Ho labelling
166Ho-DTPA, its emission β and gamma-rays.
2. claim 1
166Ho-DTPA is preparing as the application in the medicine of liquid radiation sources.
3. as claimed in claim 1
166Ho-DTPA wherein should
166Ho-DTPA is used as liquid radiation sources, is used to prevent the angioplasty operation generation of restenosis afterwards of angiostenosis disease.
4. one kind prepares
166The method of Ho-DTPA, wherein diethylene-triamine pentaacetic acid and Ho (NO
3)
3, HoCl
3Or their hydrate reaction.
5. method as claimed in claim 4 wherein comprises
166Ho+
165The Ho of Ho and the molar ratio range of diethylene-triamine pentaacetic acid were at 1: 1 to 1: 8.
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Publication number | Priority date | Publication date | Assignee | Title |
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KR100695744B1 (en) | 2005-05-03 | 2007-03-19 | 한국원자력연구소 | DTPAdiethylenetriamine pentaacetic acid derivatives and metal complexes thereof, radiation source and contrast agent including the metal complexes |
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2000
- 2000-03-31 KR KR1020000017013A patent/KR100361091B1/en not_active IP Right Cessation
- 2000-04-28 JP JP2000129737A patent/JP2001276242A/en active Pending
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2004
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JP2004217663A (en) | 2004-08-05 |
JP2001276242A (en) | 2001-10-09 |
KR20010094619A (en) | 2001-11-01 |
CN1315208A (en) | 2001-10-03 |
KR100361091B1 (en) | 2002-11-23 |
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