CN101985456A - Bone-seeking 99mTc-IPrDP coordination compound as well as preparation method and application thereof - Google Patents
Bone-seeking 99mTc-IPrDP coordination compound as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a bone-seeking 99mTc-IPrDP coordination compound, belonging to the fields of radiopharmaceuticals and nuclear medicine. The structural formula of the bone-seeking 99mTc-IPrDP coordination compound is shown in the specification. The preparation method of the coordination compound is as follows: mixing ligand IPrDP, reducing agent, pH buffer solution and pertechnetic acid (99mTcO<4->) solution to react to obtain an IPrDP coordination compound labeled by technetium-99m. The 99mTc-IPrDP coordination compound is used for nuclear medical diagnostic imaging. Through comparison, the product provided by the invention has the advantages of good product specificity, high bone/tissue intake (Am, bone) (% ID/g) and (Am, bone/Am, blood) and good tissue clearance rate, thus being expected to become novel bone imaging agent.
Description
Technical field
The present invention relates to radiopharmaceuticals and the field of nuclear medicine, specifically be meant a kind of technetium-99 m labeled diphosphonic acid complex, its preparation method and application thereof.
Background technology
Osseous tissue is made up of inorganic salt, organism and water, and the major ingredient of formation inorganic salt is hydroxyapatite [Ca
10(PO
4)
6(OH)
2] crystal, account for 2/3 of adult bone dry weight; Organism mainly is collagenous fiber and osseomucoid etc.
The bone video picture is to estimate the active common method of bone metabolism.Skeletal imaging agent enters osseous tissue may be by two kinds of approach: the one, carry out ion-exchange or chemisorption with inorganic composition in the osseous tissue; The 2nd, combine with organic component in the osseous tissue.When bone disease decreases, the sick bone that decreases the district can with blood supply what, skeletonization is vigorous or skeletonization lowly occurs or two kinds of variations of molten bone.Can deposit more crystal simultaneously at the new bone forming place that becomes bone injury.The adsorbable picture technetium of these planes of crystal-99m-methylene diphosphonate (
99mTc-MDP) skeletal imaging agent that becomes of a class makes it to show as radioactivity accumulative " hot-zone " in the bone video picture; Molten bony site then shows as " cold-zone " of radiation defect in the bone video picture.Therefore the change of (as tumour, inflammation, fracture etc.) caused regional flow and/or bone salts metabolism and osteogenetic process when the ill damage of local bone, all can in corresponding bone video picture, show local radioactivity anomaly, can make diagnosis and clearly locate various skeletal diseases in view of the above.
Two phosphonic acids are a kind of compounds that bone had obvious affinity, studies show that, calcium ion in two phosphonic hydroxyls and two phosphorus carboxyls and the bone forms the stable complex of three teeth, thereby makes two phosphonic acids be oriented to the surface of bone quickly and efficiently, and its intake in bone can be up to 50%-60%.Just because of this clear and definite target, two phosphonic acids not only are used for the treatment of osteopathy separately, can also link to each other and become bone target medicine with drug molecule, radionuclide.
May comprise aspect 4 in the two phosphonic effects of cytology level:
1) renewal metabolism, the survival of inhibition osteoclast; 2) adhesive attraction of inhibition osteoclast; 3), shorten osteoclast lifetime by apoptosis-induced; 4) suppress osteoclast activity (as Fig. 1).
The radionuclide that is successfully used to the unusual video picture of bone the most is
99mTechnetium [
99mTc].At first be because
99mThe energy of of Tc moderate (140KeV), the transformation period is lacked (transformation period is 6.02h), is suitable for video picture; Secondly, serum removes very fast; Once more, this nucleic is by reactor production, and low price can be promoted the use of.
First success
99mTc labeled phosphorus phosphate compounds is
99mTc-PYP, it is the inorganics of band P-O-P key, removing in blood and soft tissue is slower, this may be because they have higher combining with albumen in the blood, influenced the picked-up of bone to it, and the compound with P-O-P key in blood and soft tissue and the surface of bone easily by the Phosphoric acid esterase hydrolysis.1972, Perez etc. reported 1 hydroxyethanediphosphonic acid (HEDP) with
99mThe complexing of Tc substitutes [being that Sauerstoffatom (O) is replaced with carbon atom (C)] with the P-O-P key in the tetra-sodium with the P-C-P key first and obtains
99mThe diphosphonate of Tc mark; 1973, people such as Subramanian prepared
99mThe Tc-methylene diphosphonate (
99mTc-MDP); 1980, people such as Bevan prepared
99mTc-methylene radical hydroxyl diphosphonate (
99mTc-HMDP).Find that after deliberation P-C-P is arranged in the diphosphonate, and more more stable than Tripyrophosphoric acid in vivo, this is perhaps relevant with their hydrolytic actiones in vivo, simultaneously they have again the bone picked-up high and rapidly, blood and soft tissue remove fast advantage, especially
99mTc-MDP is present the most frequently used skeletal imaging agent, and this compound stability is good, bone resorption is high, serum removes soon, toxicity is low, is the ideal skeletal imaging agent.Relatively more successful at present technetium-99 m labeled two phosphonic chemical structures are shown in general structure 1.Though
99mTc-MDP is a skeletal imaging agent at present commonly used clinically, and whole body bone localization diagnosis bone shift highly sensitive in CT, MRI and X ray examination, but specificity is relatively low, therefore, is necessary the further novel diphosphonate skeletal imaging agent of research.
R＝CH2；
99mTc-methylene?diphosphonate(
99mTc-MDP)
R＝CHOH：
99mTc-hydroxymethylene?diphosphonate(
99mTc-HMDP)
R＝C(OH)CH
3：
99mTc-hydroxyethylene?diphosphonate(
99mTc-HEDP)
99mTc-1-hydroxy-2-(1H-imidazol-1-yl)ethane-1，1-diyldiphosphonicacid(
99mTc-ZL)。
Since people such as nineteen sixty-eight Fleisch found the close bone effect of diphosphonate compounds, bisphosphonates had experienced three generation products.(seeing the following form)
| Algebraically | Time | Textural difference | Representative drugs | Action intensity |
| The first-generation | The later stage sixties in last century | The last side chain of C is straight chained alkyl or has halogen to replace | Clodronate disodium (Clodronate) etidronate disodium (Etidronate) | 1 10 |
| The s-generation | 1989 | Introduce art end amino in the last side chain of C | Her this Alendronate (Ibandronate) of Pamidronate Disodium (Pamidronate) alendronate sodium (Alendronate) | 100 10000 50000 |
| The third generation | The eighties in last century | Has the ring-type side chain | Risedronate disodium (Risedronate) Zoledronic acid sodium (Zoledronate) | 1000 100000 |
By the drug efficacy study of three generations's bisphosphonates is found, in two phosphonic acids structures (as structural formula 1), be connected with the N atom on the R after, shown that good bone suppresses absorptivity, further studies show that whether contain-NH among high clinical efficacy of two phosphonic and the R
2Closely related, and contain two phosphonic acids activity of 5-7 unit aromatic amine in the R may be more much bigger than two phosphonic acids activity of aliphatic amide.It is the most active wherein to belong to imidazole ring.In the two phosphonic acids of the third generation,, be the best two phosphonic acids of present comprehensive therapeutic effect by the Zoledronic acid that contains imidazolyl heterocycle of Switzerland Novartis company research and development.It is safe and reliable again that the hypercalcemia that the Zoledronic acid of low dosage causes tumour, Parkinson's disease, bone shift the existing good curative effect of treatment of disease and post-menopausal osteoporosis, and each dosage water on average has stability and tolerance preferably in clinical, than the two phosphonic acids of the s-generation 100～800 times potentiality is arranged.
U.S. Pat 4939130 (1990) has been reported the two phosphonic acids of multiple imidazoles, one of them is chemistry 2-(imidazoles-1-yl) by name-1-hydroxyl ethane-1, the two phosphonic compounds of 1-, be Zoledronic acid (Zoledronic Acid, ZL), become best medicine (the Corey E of comprehensive therapeutic effect that bone due to the treatment hypercalcemia that causes of malignant metastatic tumor of bone and multiple myeloma and the solid tumor shifts the disease that causes at present, Brown L G, Quinn JE, et al.Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of protate cancer.Clinical Cancer Research, 2003,9,295～306.).
Zoledronic acid is the best two phosphonic acids of present comprehensive therapeutic effect, but also comes with some shortcomings, and is slower such as non-target tissue clearance rate, just can be used for problems such as clinical in 2-3 hour after the medication.Based on above achievement in research, consider that simultaneously non-target tissue such as two phosphonic parent bone performances, specificity, osteoporosis curative effect and liver absorb side reactions such as low.We are modified Zoledronic acid in plan, and synthetic its derivative is in the hope of finding the better two phosphonic acids medicines of combined therapy effect.
Summary of the invention
The technical problem to be solved in the present invention is to overcome the existing technetium-99 m labeled defective of diphosphonic acid complex on using, a kind of technetium-99 m labeled 1-hydroxyl-3-(1H-imidazoles-1-yl)-propane-1 is provided, two phosphonic acids (IPrDP) title complexs of 1-, in order to the bone video picture, its specificity is good, bone/organize the intake height, and organize clearance rate good.
In order to solve the problems of the technologies described above, the invention provides following technical scheme:
A kind of close bone
99mThe Tc-IPrDP title complex, i.e. technetium-99 m labeled 1-hydroxyl-3-(1H-imidazoles-1-the yl)-propane-1 of radioactivity, the 1-diphosphonic acid complex is abbreviated as
99mTc-IprDP, its structural formula is:
Sodium salt solution 100uL～the 300uL, the mass concentration that with mass concentration are the IPrDP of 0.3g/mL～0.5g/mL are the SnCl of 0.8mg/mL～1.2mg/mL
2Hydrochloric acid soln 70uL～160uL shakes mixing, and 20MBq～200MBq is fresh in adding
99mTcO
4 -Leacheate, transferring to pH with phosphate buffer soln is 5～7, fully shakes mixing, room temperature is placed 30min～50min, promptly gets technetium-99 m labeled 1-hydroxyl-3-(1H-imidazoles-1-yl)-propane-1, the 1-diphosphonic acid complex.
Raw material IprDP chemistry 1-hydroxyl-3-(1H-imidazoles-1-yl) by name-propane-1, the two phosphonic acids of 1-, English 1-hydroxy-3-(1H-imidazol-1-yl) propane-1 by name, 1-diyldiphosphonic acid, its structural formula is:
Parent's bone
99mThe Tc-IPrDP title complex is in the application in nuclear medicine diagnostic imaging field.
The beneficial effect of product of the present invention:
1-hydroxyl-3-(1H-imidazoles-1-yl)-propane-1 that this is technetium-99 m labeled, the 1-diphosphonic acid complex improves Zoledronic acid class medicine, has promptly expanded the connecting arm between imidazolyl and the diphosphonate, and expectation obtains the over-all properties better medicament.Experimental result shows: osseous tissue intake height, residence time are long in the early stage, and except kidney, in other non-target tissue, especially the aggregate concentration in liver, the spleen has the reduction of highly significant than Zoledronic acid class medicine.Simultaneously, with the technetium-99 m labeled methylene-bis phosphonic acids of document [Liu Liqin etc., Beijing Normal University's journal (natural science edition), 230～233 pages of the 39th the 2nd phases of volume of April in 2003] report (
99mTc-MDP) and we the early stage result of study
99mTc-ZL (the patent No.: 200510038174.8 publication numbers: CN1680409A) compare the osseous tissue intake (A of product of the present invention
m, bone) and (%ID/g) and (A
m, bone/A
m, blood) and than literature value height, and organize clearance rate fast than bibliographical information, illustrate that product of the present invention has more the potential as skeletal imaging agent.
Description of drawings
Accompanying drawing is used to provide further understanding of the present invention, and constitutes the part of specification sheets, is used from explanation the present invention with embodiments of the invention one, is not construed as limiting the invention.In the accompanying drawings:
Fig. 1 is the two phosphonic effect synoptic diagram of cytology level that background technology of the present invention is mentioned;
Fig. 2 is of the present invention
99mThe rabbit bone video picture figure of Tc-IPrDP.
Embodiment
Below in conjunction with accompanying drawing the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for description and interpretation the present invention, and be not used in qualification the present invention.
Technetium-99 m labeled 1-hydroxyl-3-(1H-imidazoles-1-yl)-propane-1, the 1-diphosphonic acid complex (
99mTc-IPrDP) preparation and performance measurement thereof.
1)
99mThe preparation of Tc-IPrDP
(a) 1-hydroxyl-3-(1H-imidazoles-1-yl)-propane-1, the preparation of two phosphonic acids (IPrDP) parts of 1-: with the imidazoles is raw material, is performed as follows three-step reaction and obtains the target new compound.
The building-up reactions route of IPrDP
The structural confirmation of target compound IPrDP:
Fusing point: 242-245 ℃ of product fusing point;
Ultimate analysis (C
6H
12N
2O
7P
2):
| Element | C | H | N |
| Calculated value (%) | 25.19 | 4.23 | 9.79 |
| Measured value (%) | 25.27 | 4.38 | 9.84 |
Mass spectrum (FAB): 285 (M-1);
Infrared (IR): 3148 (v
C-H), 3500-2600 (v
O-H), 1603 (v
C=C), 1337 (v
C-N), 1098 (v
P=O);
1The H nuclear magnetic resonance spectrum (
1HNMR):
(b)
99mThe preparation of Tc-IPrDP: the sodium salt solution 100uL, the mass concentration that with mass concentration are the IPrDP of 0.5g/mL are the SnCl of 1mg/mL
2Hydrochloric acid soln 70uL shakes mixing, and 200MBq is fresh in adding
99mTcO
4 -Leacheate, transferring to pH with phosphate buffer soln is 7, fully shakes mixing, room temperature is placed 50min, promptly gets technetium-99 m labeled 1-hydroxyl-3-(1H-imidazoles-1-yl)-propane-1, the 1-diphosphonic acid complex.
2)
99mThe mensuration of Tc-IPrDP mark rate
Thin-layer chromatography chromatography (TLC), paper of Xinhua is upholder, adopts acetone and deionized water to make developping agent respectively.Mark rate reaches 95.8% (greater than 95%) after measured.
Each component tomographic results (Rf value)
3)
99mThe mensuration of the vitro stability of Tc-IPrDP
Because the transformation period of technetium-99m is 6h, therefore, freshly prepd technetium-99 m labeled IPrDP is placed room temperature (25 ± 2 ℃), (1,2,3,4,5,6h) sampling analysis is investigated technetium-99 m labeled IPrDP shelf stability at room temperature to different time.Experimental result shows,
99mTc-IPrDP at room temperature deposits 6h, and its mark rate is still greater than 95%, and outward appearance has no significant change, and all can satisfy the requirement of clinical application.
4)
99mTc-IPrDP is in the intravital bio distribution of mouse
Prepare mark rate greater than 95% according to present embodiment
99mTc-IPrDP solution.(male and female are regardless of, and body weight 18～20g) is divided into 7 groups at random, 6 every group with 42 normal ICR mouse.Through the about 1.0MBq of tail vein injection 0.2mL
99mBehind the Tc-IPrDP, in 5,10,15,30,60,120 and 240min sacrificed by decapitation mouse.Core, liver, spleen, lung, kidney, bone, joint, muscle, sexual gland, intestines, stomach, brain, blood, measure radiocounting with the γ calculating instrument after weighing, and the radiocounting of calculating every gram internal organs accounts for the ratio of the percentage ratio (%ID/g) of implantation dosage and bone and the radioactivity of each tissue, and the quality of the whole blood of mouse is calculated by 6.5% of its body weight.Each the time get 5 groups of panel datas mutually, experimental result is represented with mean value.Absorb in the different time points osseous tissue
99mAmount (the A of Tc-IPrDP
m,
Bone) (%ID/g) be respectively 5.37,6.64,6.79,7.78,11.2,6.80,8.46; In the corresponding time blood
99mThe amount of Tc-IPrDP (Am, blood) (%ID/g) is respectively 6.99,3.48,3.04,1.41,0.69,0.22,0.09; Am, bone/Am, blood is respectively 0.76,1.91, and 2.18,5.47,16.1,30.8,94.0.And the technetium-99 m labeled methylene-bis phosphonic acids of document [Liu Liqin etc., Beijing Normal University's journal (natural science edition), 230～233 pages of the 39th the 2nd phases of volume of April in 2003] report (
99mTc-MDP) 30,60,120 and the osseous tissue during 180min in the amount (A that absorbs
m,
Bone) (%ID/g) be respectively 3.26,4.79,3.87,7.71; In the corresponding time blood
99mAmount (the A of Tc-MDP
m,
Blood) (%ID/g) be respectively 0.47,0.28,0.15,0.12; A
m,
Bone/ A
m,
BloodBe respectively 6.91,17.31,26.22,67.34.In conjunction with patent (application number: 200510038174.8 publication numbers: the removing situation of soft tissue CN1680409A) in the technetium-99 m labeled Zoledronic acid of report, concrete data see Table 1:
The comparison that clears data of the mouse in-vivo tissue of each medicine of table 1.
As can be seen from the table,
99mTc-IPrDP is when injection 30min, 60min, 120min, and the intake of osseous tissue (ID%/g) is respectively 7.72,11.2,6.80; Show that its medicine has good picked-up and delay in osseous tissue.In addition, corresponding time blood intake is respectively 1.41,0.69,0.22; The liver intake is respectively 5.69,4.12,3.77; Embody the ratio of good bone and non-target organs, compare with MDP and ZL, this medicine osseous tissue intake height, residence time in the early stage is long, except kidney, in other non-target tissue, especially the aggregate concentration in liver, the spleen has the reduction of highly significant, is expected to become a kind of novel skeletal imaging agent.
5)
99mThe rabbit bone video picture of Tc-IPrDP
After new zealand rabbit intramuscular injection stable (2mL) and ketamine (2mL) anesthesia, inject by auricular vein
99mTc-IPrDP150MBq (2.5mL) carries out the SPECT video picture.The video picture of Fig. 2 rabbit is the result show: in injection
99mBehind the Tc-IPrDP 60min, rabbit bone imaging results is good, and skull, backbone and four limbs video picture are obvious, and soft tissue is removed substantially, and background is few.
99mTc-IPrDP can obtain image clearly behind injection 60min, its excellent properties as novel skeletal imaging agent has obtained further confirmation.
What deserves to be explained is, adopt in the test
99mThe preparation method of Tc-IPrDP also has:
1, be that sodium salt solution 300uL, the mass concentration of the IPrDP of 0.3g/mL is the SnCl of 0.8mg/mL with mass concentration
2Hydrochloric acid soln 100uL, concussion mix, and 150MBq is fresh in adding
99mTcO
4 -Leacheate, transferring to pH with phosphate buffer soln is 6, fully shakes mixing, room temperature is placed 40min, promptly gets technetium-99 m labeled 1-hydroxyl-3-(1H-imidazoles-1-yl)-propane-1, the 1-diphosphonic acid complex.
2, be that sodium salt solution 200uL, the mass concentration of the IPrDP of 0.4g/mL is the SnCl of 1.2mg/mL with mass concentration
2Hydrochloric acid soln 160uL shakes mixing, and 40MBq is fresh in adding
99mCO
4 -Leacheate, transferring to pH with phosphate buffer soln is 5, fully shakes mixing, room temperature is placed 30min, promptly gets technetium-99 m labeled 1-hydroxyl-3-(1H-imidazoles-1-yl)-propane-1, the 1-diphosphonic acid complex.
These two kinds of method preparations
99mTc-IPrDP is by above-mentioned 2), 3), 4), 5) determination of experimental method, further confirmed its superiority as novel skeletal imaging agent.
It should be noted that at last: the above only is the preferred embodiments of the present invention, be not limited to the present invention, although the present invention is had been described in detail with reference to previous embodiment, for a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment put down in writing, and perhaps part technical characterictic wherein is equal to replacement.Within the spirit and principles in the present invention all, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (3)
1. close bone
99mThe Tc-IPrDP title complex, its structural formula is:
2. the described close bone of claim 1
99mThe preparation method of Tc-IPrDP title complex is that sodium salt solution 100uL～300uL, the mass concentration of the IPrDP of 0.3g/mL～0.5g/mL is the SnCl of 0.8mg/mL～1.2mg/mL with mass concentration
2Hydrochloric acid soln 70uL～160uL shakes mixing, and 20MBq～200MBq is fresh in adding
99mTcO
4 -Leacheate, transferring to pH with phosphate buffer soln is 5～7, fully shakes mixing, room temperature is placed 30min～50min, promptly gets technetium-99 m labeled 1-hydroxyl-3-(1H-imidazoles-1-yl)-propane-1, the 1-diphosphonic acid complex.
3. the described close bone of claim 1
99mThe Tc-IPrDP title complex is in the application in nuclear medicine diagnostic imaging field.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102603812A (en) * | 2012-03-09 | 2012-07-25 | 江苏省原子医学研究所 | Binuclear platinum (II)-zoledronate complex and preparation and application thereof |
| CN102617642A (en) * | 2012-02-24 | 2012-08-01 | 江苏省原子医学研究所 | Biphosphate compound containing2-ethyl imidazole as well as preparation method and application thereof |
| CN102731580A (en) * | 2012-07-12 | 2012-10-17 | 江苏省原子医学研究所 | Binuclear platinum (II)-diphosphonic acid coordination compound, preparation method and application thereof |
| CN105175454A (en) * | 2015-10-29 | 2015-12-23 | 北京师范大学 | 99mTcN nucleus mark alendronic acid dithiocarbamate complex and preparation method and application thereof |
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| CN1680409A (en) * | 2005-01-18 | 2005-10-12 | 江苏省原子医学研究所 | Diphospho-acid complex of radiative technetium-99m marked oxazole phosphinic acid |
| CN101693724A (en) * | 2009-10-09 | 2010-04-14 | 江苏省原子医学研究所 | Technetium-99m labeled propyl zoledronic acid composition and preparation method thereof |
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2010
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1680409A (en) * | 2005-01-18 | 2005-10-12 | 江苏省原子医学研究所 | Diphospho-acid complex of radiative technetium-99m marked oxazole phosphinic acid |
| CN101693724A (en) * | 2009-10-09 | 2010-04-14 | 江苏省原子医学研究所 | Technetium-99m labeled propyl zoledronic acid composition and preparation method thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617642A (en) * | 2012-02-24 | 2012-08-01 | 江苏省原子医学研究所 | Biphosphate compound containing2-ethyl imidazole as well as preparation method and application thereof |
| CN102603812A (en) * | 2012-03-09 | 2012-07-25 | 江苏省原子医学研究所 | Binuclear platinum (II)-zoledronate complex and preparation and application thereof |
| CN102603812B (en) * | 2012-03-09 | 2015-11-18 | 江苏省原子医学研究所 | A kind of Binuclear platinum (II) – Zoledronic acid title complex and Synthesis and applications thereof |
| CN102731580A (en) * | 2012-07-12 | 2012-10-17 | 江苏省原子医学研究所 | Binuclear platinum (II)-diphosphonic acid coordination compound, preparation method and application thereof |
| CN102731580B (en) * | 2012-07-12 | 2015-07-01 | 江苏省原子医学研究所 | Binuclear platinum (II)-diphosphonic acid coordination compound, preparation method and application thereof |
| CN105175454A (en) * | 2015-10-29 | 2015-12-23 | 北京师范大学 | 99mTcN nucleus mark alendronic acid dithiocarbamate complex and preparation method and application thereof |
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