CN100469781C - Double phospho acid compound of 99mT.C. mark and preparation method - Google Patents
Double phospho acid compound of 99mT.C. mark and preparation method Download PDFInfo
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- CN100469781C CN100469781C CN 200610040896 CN200610040896A CN100469781C CN 100469781 C CN100469781 C CN 100469781C CN 200610040896 CN200610040896 CN 200610040896 CN 200610040896 A CN200610040896 A CN 200610040896A CN 100469781 C CN100469781 C CN 100469781C
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Abstract
This invention relates to a preparation method of technetium - 99m noted 2 - ( 1 - methyl glyoxaline - 2 - group) - 1 - hydroxy ethane - 1, 1 - double phosphonic acid complex, belongs to radiopharmaceuticals and nuclear medicine region. It uses ligand double phosphonic acid ( HMIBP), reducer, pH buffering agent and so on to compose drug box, then add high technetium acid ( 99mTcO4 -) solution to drug box for reaction, obtain technetium - 99m labeled 2 - ( 1 - methyl glyoxaline - 2 - group) - 1 - hydroxy ethane - 1, 1 - double phosphonic acid complex ( 99mTc - HMIBP). This technetium - 99m labeled double phosphonic acid complex used for nuclear medicine diagnose discovery or Rheumatoid and tumour treatment, and so on. The osseous tissue intake dose ( Am, bone) (%ID / g) and ( Am, bone / Am, blood) ratio of this invention is higer than literature value, illustrate that this invention has better effect as bone developer.
Description
Technical field
Technetium-99 m labeled 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1,1-diphosphonic acid complex and preparation method relate to radiopharmaceuticals and the field of nuclear medicine.
Background technology
Sclerotin is by osteocyte, and gelatinous fiber and ground substance of bone three parts are formed.Ground substance of bone is made up of inorganic salt and organism.Inorganic salt account for 2/3 of adult's sclerotin, and its major ingredient is hydroxyapatite crystal [Ca
10(PO
4)
6(OH)
2], having bigger surface-area, similar a kind of ion exchange resin can exchange or adsorbs with corresponding ion in mode such as ion-exchange or surface adsorption and the blood.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 precipitate more crystal simultaneously at the new bone forming place that becomes bone injury.The developer of adsorbable picture 99mTc-MDP one class of these planes of crystal 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 blood 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.Therefore, the bone video picture has obtained a large amount of application in clinical, is mainly used in following situation: the early diagnosis that the soft tissue of (1) primary bone tumor and bone tumor and bone shift; (2) check agnogenic ostalgia; (3) select bone histopathologic examination position; (4) formulate radiotherapy planning; (5) reach following up a case by regular visits to after the treatment before the art of other system tumours such as lymphoma, mammary cancer, lung cancer, prostate cancer by stages; (6) the suspected tumor patient is screened; (7) diagnosis of bone inflammatory lesion and following up a case by regular visits to; (8) differential diagnosis of osteoarthrosis such as stress fracture, ischemic osteonecrosis wound; (9) following up a case by regular visits to after the level diagnosis of Paget disease and the treatment.
Since Subramanian in 1971 etc. have introduced
99mThe polyphosphate of Tc mark has been used for since the video picture, a large amount of radionuclide technetium-99m[occurred
99mTc] bisphosphonates of mark is used for the skeletal imaging agent, makes the research of bone iconography tracer agent that very great development arranged.Radionuclide technetium-99m[
99mTc] widespread use at first be because
99mThe energy of of Tc is 140KeV (energy is moderate), and the transformation period is lacked (transformation period is 6.02h), is suitable for video picture; Secondly, this nucleic is by reactor production, and low price can be promoted the use of.
Use the earliest
99mThe polyphosphate of Tc mark success is
99mTc mark tetra-sodium (
99mTc-PYP), PYP is the inorganics of band P-O-P key, with hydroxyapatite in the human body bone identical structure is arranged, thereby it is fast with synosteosis, but pyrophosphate salt is oral invalid, injection is again easily by the enzymic hydrolysis in the human body and instability, thereby the P-O in the tetra-sodium-P key is substituted [be Sauerstoffatom (O) with carbon atom (C) replacement] acquisition with P-C-P key
99mThe diphosphonate of Tc mark, such diphosphonate have fast with synosteosis in vivo, are difficult for by the characteristics of enzymic hydrolysis again, thereby have better chemical stability, and therefore thermotolerance is widely used in clinical video picture.Common skeletal imaging agent has
99mTc-MDP,
99mTc-HMDP,
99mTc-HEDP etc., chemical structure is shown in general structure 1.At present the most generally be used for clinical bone video picture be technetium-99 m labeled methylene-bis phosphonic acids (
99mTc-MDP), it can be by bone resorption, and active or reactive osseous lesion district concentration is higher at bone metabolism, time of developing is also longer, is the most frequently used skeletal imaging agent at present.Though
99mTc-MDP is a skeletal imaging agent at present commonly used clinically, and whole body bone localization diagnosis metastatic tumor of bone is 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＝CH
2：
99mTc-methylene?diphosphonate(
99mTc-MDP)
R＝CH-OH：
99mTc-hydroxymethylene?diphosphonate(
99m?Tc-HMDP)
R＝CH
3-C-OH：
99mTc-hydroxyethylene?diphosphonate(
99mTc-HEDP)
General structure 1
Since people such as nineteen sixty-eight Fleisch found the close bone effect of diphosphonate compounds, bisphosphonates had experienced three generation products.First-generation research starts from the later stage sixties in last century, side chain is straight chained alkyl or has halogen to replace in its structure, (Finland Leiras pharmaceutical factory produces clodronate disodium (Clodronate), Initial Public Offering in 1986, commodity are called Bonefos) and etidronate disodium (Etidronate) (the seventies goes on the market in the U.S., now record in American Pharmacopeia) be its representative, the gap of its effective dose and toxic dose is that safety range is narrow; S-generation medicine is introduced terminal amino group in side chain, as Pamidronate Disodium (Pamidronate) (Switzerland Ciba-Geigy company exploitation, Initial Public Offering in 1989, commodity are called Aredia), alendronate sodium (Alendronate) (U.S. Merck company exploitation, commodity are called Fosmax), her this Alendronate (Ibandronate) and Olpadronic acid sodium (olpadronate).The third generation was developed the eighties in last century, its structure has the ring-type side chain, comprise tiludronic acid disodium (Tiludronate), Incadronate (YM-175), (the Switzerland Novartis Co.,Ltd exploitation of Risedronate disodium (Risedronate) and Zoledronic acid sodium (Zoledronate), 2000 first at Canada's listing, trade(brand)name Zometa).
One of third generation diphosphonate Incadronate is by the exploitation of Japanese Yamanouchi company, in 1997 in Japan's listing, clinical indication is the hypercalcemia that malignant metastatic tumor of bone causes.We have also succeeded in developing and have been used for the treatment of the pain that malignant metastatic tumor of bone causes and " the injection Incadronate " of hypercalcemia.External existing document (Makoto S, Susumu S, Hiroshi I.New bone-seeking agent:Animal study ofTc-99m-incadronate.Annals of Nuclear Medicine, 2002; 16:55～59) with the report of technetium-99 m labeled Incadronate as skeletal imaging agent.
U.S. Pat 4939130 (1990) has been reported the two phosphonic acids of multiple imidazoles, one of them, chemistry 2-(imidazoles-1-yl) by name-1-hydroxyl ethane-1, the two phosphonic compounds of 1-, be Zoledronic acid (ZoledronicAcid), 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 LG, Quinn JE, etal.Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolyticmetastases of protate cancer.Clinical Cancer Research, 2003; 9:295～306).We apply for a patent (number of patent application: 200510038174.8) report with technetium-99m (
99mTc) mark Zoledronic acid and 2-(glyoxal ethyline-1-yl)-1-hydroxyl ethane-1, the two phosphonic acids of 1-(are abbreviated as
99mTc-MIDP), and carry out the bone video picture, obtain effect preferably.We are with technetium-99 m labeled 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1 now, the two phosphonic acids of 1-, in view of its structure similar with MIDP, but difference (two phosphonic acids are to be connected on the 2-position of imidazole ring) fully, expectation is a skeletal imaging agent likely, does not all see any report at present both at home and abroad.
Summary of the invention
The objective of the invention is to propose a kind of novel skeletal imaging agent: technetium-99 m labeled 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the 1-diphosphonic acid complex (
99mTc-HMIBP).Simultaneously, the invention allows for the preparation method of this technetium-99 m labeled diphosphonic acid complex, and it in human or animal's organ or tissue as the purposes of developer, in particular as skeletal imaging agent.
Technical scheme of the present invention:
2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the two phosphonic chemical structures of 1-are shown in structural formula 2:
Structural formula 2
Its English 2-(1-methylimidazol-2-yl) by name-1-hydroxyethane-1,1-bisphosphonic acid is abbreviated as HMIBP.
The invention provides the technetium-99 m labeled 2-of a kind of radioactivity (1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the 1-diphosphonic acid complex is abbreviated as
99mTc-HMIBP, its structure is shown in structural formula 3
Structural formula 3
Its preparation method is: at first this pair phosphonic acids and a certain amount of reductive agent, pH buffer reagent are mixed with medicine box, add an amount of high technetium acid solution again, with mixture jolting number minute, promptly obtain technetium-99 m labeled diphosphonic acid complex.Reductive agent is tin protochloride (SnCl
2.2H
2O) want or vitamins C etc.
Technetium-99 m labeled 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the two phosphonic preparation methods of 1-are: in cillin bottle, add 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the two phosphonic acids 3～5mg of 1-add and contain 1.0gL
-1SnCl
22H
2The 0.1molL of O
-1Hydrochloric acid soln 0.05～0.25mL, phosphate buffer soln with pH4.3 after shaking up is adjusted to pH4～6, high technetium-99m acid solution 18.5～185 megabecquerels that add new drip washing, abundant mixing, room temperature was placed 8～15 minutes, promptly obtain described technetium-99 m labeled 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the 1-diphosphonic acid complex.
This technetium-99 m labeled diphosphonic acid complex is used for the diagnostic imaging of nuclear medicine, also can be used for the treatment of diseases such as similar rheumatism, tumour.
Beneficial effect of the present invention: the present invention proposes a kind of new two phosphonic acids skeletal imaging agents--technetium-99 m labeled 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the 1-diphosphonic acid complex, chemical structure to Zoledronic acid and MIDP is modified, and comes mark with technetium-99m.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) relatively, the osseous tissue intake (A of product of the present invention
M, bone) (%ID/g) and (A
M, bone/ A
M, blood) than literature value height, illustrate that product of the present invention can be better as the effect of skeletal imaging agent.
Embodiment
Technetium-99 m labeled 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the 1-diphosphonic acid complex (
99mTc-HMIBP) preparation and performance measurement thereof
1)
99mThe preparation of Tc-HMIBP
In the 10ml cillin bottle, add 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the two phosphonic acids 3～5mg of 1-, SnCl
22H
2(concentration of hydrochloric acid is 0.1molL to hydrochloric acid soln 0.05～0.25mL of O
-1, include 1.0gL
-1SnCl
22H
2O), shake up the back be adjusted to pH4～6 with phosphate buffer soln (pH4.3), add new drip washing high technetium-99m acid (
99mTcO
4 -) solution 18.5～185 megabecquerels (MBq), abundant mixing, room temperature was placed 8～15 minutes, and mark finishes, and promptly gets technetium-99 m labeled 2-of the present invention (1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the 1-diphosphonic acid complex (
99mTc-HMIBP).
2)
99mThe mensuration of Tc-HMIBP mark rate
The mark rate of technetium-99 m labeled imidazoles diphosphonic acid complex is meant in the system
99mThe radioactivity of Tc-HMIBP accounts for the per-cent of gross activity.The employing Paper Chromatography is measured: system (1) is acetone: water=2:1; System (2) is a water.In the system (1), the colloid technetium and
99mThe Rf value of Tc-HMIBP is 0,
99mTcO
4 -The Rf value be 0.9-1.0; In the system (2), the Rf value of colloid technetium is 0-0.1,
99mTc-HMIBP and
99mTcO
4 -The Rf value be 0.9-1.0.According to formula
99mThe mark rate of Tc-HMIBP (RCP)=(1-RCP
The colloid technetium-RCP
Trip From technetium) * 100%, the result shows:
99mThe mark rate of Tc-HMIBP is greater than 95%.(wherein RCP represents radiochemical purity, i.e. mark rate).
3)
99mThe mensuration of the vitro stability of Tc-HMIBP
Because the transformation period of technetium-99m is 6.02 hours, therefore, with freshly prepd technetium-99 m labeled 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the two phosphonic acids of 1-place room temperature, and different time (1,2,3,4,5 and 6 hour) sampling analysis is investigated
99mTc-HMIBP shelf stability at room temperature.Experimental result shows: technetium-99 m labeled 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, after the two phosphonic acids of 1-were at room temperature deposited 6 hours, its mark rate and outward appearance had no significant change, and still can satisfy the requirement of clinical application.
4)
99mTc-HMIBP is in the intravital bio distribution of mouse
Prepare mark rate greater than 95% according to embodiment 1
99mTc-HMIBP solution.30 normal mouses (male and female are regardless of, body weight 18～20 grams) are divided into 6 groups at random, from tail vein injection 0.1mL (about 0.74～1.85MBq)
99mTc-HMIBP solution is then respectively at injecting back 5,15,30,60,120 and 240 minutes with the mouse sacrificed by decapitation.Get related organization and organs such as its heart, liver, spleen, lung, kidney, muscle, bone and blood, in trap type gamma ray probe, measure radioactivity after weighing, the radioactivity of calculating every gram tissue accounts for the ratio of the percentage ratio of total injected dose (%ID/g) 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 osseous tissue
99mAmount (the A of Tc-HMIBP
M, bone) (%ID/g) be respectively 4.98,6.84,7.94,7.45,5.87,4.19; In the corresponding time blood
99mAmount (the A of Tc-HMIBP
M, blood) (%ID/g) be respectively 2.40,1.07,0.47,0.12,0.05,0.02; A
M, bone/ A
M, bloodBe respectively 2.08,6.39,16.89,62.08,117.40, the technetium-99 m labeled methylene-bis phosphonic acids of 209.50. and 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) amount (A that absorbs in the osseous tissue when 30 minutes, 60 minutes, 120 minutes and 180 minutes
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.Patent (application number: the technetium-99 m labeled MIDP of report 200510038174.8) (
99mTc-MIDP) at 5 minutes, 15 minutes, the amount (A that absorbs in the osseous tissue when 30 minutes, 60 minutes, 120 minutes and 180 minutes
M, bone) (%ID/g) be respectively 14.30,11.78,8.50,7.95,11.29,13.88; Absorb in the corresponding time blood
99mAmount (the A of Tc-MIDP
M, blood) (%ID/g) be respectively 6.18,2.54,0.69,0.34,0.145,0.099; A
M, bone/ A
M, bloodBe respectively 2.31,4.64,12.32,23.38,77.86,140.20.
5)
99mThe rabbit bone video picture of Tc-HMIBP
Get new zealand rabbit, intramuscular injection stable (10mg/ props up, 2ml) 1 and chlorine peace ketone (.0.1g/ props up, 2ml) half, behind the anesthesia 20min, in auricular vein injection 0.5ml
99Tc
m-HMIBP (about 111MBq) carries out the bone scanning of SPECT whole body rabbit.The result shows: injected back 120 minutes, rabbit bone imaging results is good, skull, and backbone and four limbs video picture are obvious, and soft tissue is removed substantially.
Claims (2)
1. 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1 that radioactivity is technetium-99 m labeled, the 1-diphosphonic acid complex is abbreviated as
99mTc-HMIBP, its structural formula is:
2. the described technetium-99 m labeled 2-of claim 1 (1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the preparation method of 1-diphosphonic acid complex is characterized in that: in cillin bottle, add 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the two phosphonic acids 3～5mg of 1-add and contain 1.0gL
-1SnCl
2.2H
2The 0.1molL of O
-1Hydrochloric acid soln 0.05～0.25mL, phosphate buffer soln with pH4.3 after shaking up is adjusted to pH4～6, high technetium-99m acid solution 18.5～185 megabecquerels that add new drip washing, abundant mixing, room temperature was placed 8～15 minutes, promptly obtain described technetium-99 m labeled 2-(1-Methylimidazole-2-yl)-1-hydroxyl ethane-1, the 1-diphosphonic acid complex.
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| CN101538284B (en) * | 2009-05-05 | 2011-09-07 | 北京师范大学 | Preparation method and application of 99Tcm-EDTA-MTI coordination compound |
| CN114689739B (en) * | 2022-01-30 | 2023-10-03 | 江苏省原子医学研究所 | 99m Separation method of Tc-TRODAT-1 diastereoisomer |
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Non-Patent Citations (4)
| Title |
|---|
| 《99Tcm－MIDP的制备及其生物学分布》. 罗世能等.《中华核医学杂志》，第25卷第6期. 2005 |
| 《99Tcm－MIDP的制备及其生物学分布》. 罗世能等.《中华核医学杂志》，第25卷第6期. 2005 * |
| 《新型骨显像剂 99Tcm-ZL 的制备和动物实验研究》. 王洪勇等.《核技术》，第29卷第6期. 2006 |
| 《新型骨显像剂 99Tcm-ZL 的制备和动物实验研究》. 王洪勇等.《核技术》，第29卷第6期. 2006 * |
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