CN1131071C - Tissue anoxia developing agent and its precursor - Google Patents
Tissue anoxia developing agent and its precursor Download PDFInfo
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- CN1131071C CN1131071C CN 01110037 CN01110037A CN1131071C CN 1131071 C CN1131071 C CN 1131071C CN 01110037 CN01110037 CN 01110037 CN 01110037 A CN01110037 A CN 01110037A CN 1131071 C CN1131071 C CN 1131071C
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- developing agent
- tissue
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- nitroimidazole
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Abstract
The present invention relates to a tissue anoxia developing agent and a precursor thereof which is an aromatic amino oxime compound with nitro groups. The compound is used as a ligand to form a coordination compound with technetium-99m to obtain a technetium-99m amino oxime anoxia developing agent. The anoxia developing agent with good hydropathicity is synthesized easily, used for obviously improving the developing quality of the anoxia tissue, and widely used in the medical developing field.
Description
Technical field:
The present invention relates to a kind of precursor that has the amino oximes radioactive compound of hypoxic tissue video picture function and prepare this chemical compound, particularly a kind of tissue anoxia developing agent and precursor thereof that contains the nitryl aromatic base.
Background technology:
Tissue anoxia is a principal character of multiple important diseases clinically, and the tissue oxygen level is very important in the diagnosis of these diseases.Owing to measure the difficulty of anoxia shape in the body, limited its application clinically in the past.Adopt the non-invasi method to determine that hypoxic tissue is subjected to extensive attention always, nuclear medicine technology is to utilize the hypoxic tissue developer to carry out single photon emission computerized tomography (SPECT) or positron emission tomography (PET).This technology is simple and easy to do, is very suitable for clinical application.
As the nitro glyoxaline compound of radiosensitizer, it depends on available oxygen amount in the tissue in intracellular metabolism.Utilize this specific character, can use this compounds of radioisotope labeling, be used for the video picture of hypoxic tissue, thus reach clinical diagnosis purpose (Nunn, A., et al., Eur.J.Nucl.Med., 1995,22:265).As far back as the initial stage eighties, (Garreeht such as Chapman, B.M., Chapman, J.D., Br.J.Radiol., 1983,26:745) just propose, radiolabeled nitro-aromatics can provide a kind of non-interventional technique, promptly uses external imaging method (PET or SPECT) to measure the level of oxygen in the tissue.Carbon-14 (
14C), hydrogen-3 (
3H), fluoro-18 (
18F), bromo-82 (
82Br) and the video picture that has been used for weary oxygen cardiac muscle and tumor of radioiodinated 2-nitroimidazole study (Nunn, A., et al., Eur.J.Nucl.Med., 1995,22:265; Schneider, R.F., et al., Quarterly J.Nucl.Med., 1995,39:41; Groshar, D., et al., J.Nucl.Med., 1993,34:885; Al-Arafaj, A., et al., Eur, J.Nucl.Med., 1994,21:1338; Yeh, S.H., et al., J.Nucl.Med., 1994,35:205; Webb, P., et al., J.Labelled Compd.Radiopharm., 1990,28:257; Tewson, T.J., Nucl.Med.Biol., 1997,24:755-760; Piert, M., et al., Eur.J.Nucl.Med., 1999,26:95).Yet difficult acquisition of these radionuclides and expensive PET picture reproducer are seriously restricting the broad research and the application of these medicines.
Synthesized in recent years a series of technetium-99m (
99mTc) the 2-nitroimidazole complex of labelling, adopting the adduct (BATO) of technetium-two oxime complex and boric acid and propylidene amidoxime (PnAO) compounds respectively is bifunctional linking reagent (Nunn, A., et al., Eur.J.Nucl.Med., 1995,22:265), the one end with
99mThe Tc chelating, the other end and 2-nitroimidazole join.
Although the BATO-nitro glyoxaline compound has the nitro that can be discerned by xanthine oxidase, because the nitroimidazole that is not labeled and the existence of substituted boracic acid, it is unsatisfactory with the bonded speed of hypoxic tissue in vivo.Studies show that the BATO analog of fat-solubility may be trapped in the hydrophobic membrane, and do not enter cytosol (Nunn, A., et al., Eur.J.Nucl.Med., 1995,22:265).
Linder in 1994 etc. are synthetic
99mTc-[PnAO-1-(2-nitroimidazole)] (be BMS181321, Fig. 1) (Linder, K.E., et al., J.Med.Chem., 1994,37:9), (also claim BRU 59-2, Fig. 2), this is to study maximum class hypoxic tissue developers at present to synthesize BMS194796 later on again.Ballinger etc. (Ballinger, J.R., et al., J.Nucl.Med., 1996, result of study 37:1023) shows that BMS181321 can be used for the clinical research of entity tumor anoxia state.Yet, Rumsey etc. (Rumsey, W.L., et al., J.Nucl.Med., 1995,36:1445) find, owing to the fat-solubility of BMS181321 causes its removing slowly and high background in vivo.Discoveries such as Shi, although by external SPECT video picture, the cardiac muscle that can detect Canis familiaris L. has higher delay to BMS181321, but the low heart/liver concentration ratio makes it be difficult to planar imaging, and this has also limited its myocardial imaging (Shi, C.Q.-X. in clinical, et al., J.Nucl.Med., 1995,36:1078).
Amino oxime is owing to synthesize simply easy and some metal ion nickel (Ni
2+), copper (Cu
2+), silver (Ag
+), cobalt (Co
2+) wait and form colored stable coordination compound.A long time ago, just be used as a kind of analytical reagent, even can be used for doing quantitative analysis (Eloy, F., et al.Chem.Rev., 1962,62:155).But a research group of Japan just is used for labelling with amino oxime up to date
99mTc (Nakayama, M., et al., Nucl.Med.Commun., 1992,13:445; Nakayama, M., et al., Appl.Radiat.lsot., 1994,45:735).
In a word, anoxia developing agent is fat-soluble too high at present, and synthetic route is long, awaits further improvement.
Summary of the invention:
The purpose of this invention is to provide a kind of syntheticly simple, good hydrophilic property can obviously be improved the anoxia developing agent of hypoxic tissue video picture quality.
Tissue anoxia developing agent of the present invention comprises the amino oxime part of nitryl aromatic, goes back the technetium-99m of ortho states, and the coordination structure of this part and technetium-99m formation, has following structural formula:
Wherein, R represents the nitryl aromatic group; R ' is C
0～C
8Alkylidene, or cycloalkylidene, or alkenylene, or alkynylene, perhaps their substituent; R " be H, or alkyl, perhaps substituted alkyl.The precursor of preparation tissue anoxia developing agent of the present invention, its structure is:
Wherein, R represents the nitryl aromatic group, and R ' represents C
0～C
8Alkylidene, cycloalkylidene, alkenylene, alkynylene or its substituent; R ' more can be an ethylene group; R " be H, or alkyl, perhaps substituted alkyl.The nitroimidazole that R can be nitroimidazole or is substituted is 2-nitroimidazole or 4-nitroimidazole such as R.
The synthetic class of the present invention has the precursor of the amino oxime of aromatic series of nitro as tissue anoxia developing agent, and synthetic have only two to go on foot and be very easy to; This developer good hydrophilic property, the distribution ratio of n-octyl alcohol and water are 0.04, and the distribution ratio of BMS181321 is up to 40;
99mTc has good nulcear properties, is the most frequently used radionuclide of current nuclear medicine image, and labelling can be finished and the mark rate height at short notice.The tissue anoxia developing agent made from this precursor can obviously improve the video picture quality of hypoxic tissue because its special construction (see figure 3).
Fig. 4 is relatively seen in distribution in the animal body of tissue anoxia developing agent of the present invention and existing anoxia developing agent.
Description of drawings
Fig. 1 BMS181321 structure chart
Fig. 2 BMS194796 structure chart
The tissue anoxia developing agent structure chart that Fig. 3 is a kind of to have a feature of the present invention wherein, R represents the nitryl aromatic group; R ' is C
0～C
8Alkylidene, or cycloalkylidene, or alkenylene, or alkynylene, perhaps their substituent; R " be H, or alkyl, perhaps substituted alkyl.
Distribute relatively in the animal body of Fig. 4 the present invention and existing anoxia developing agent
Animal is a tumor-bearing mice in this table, and data are taken from back 2 hours of injection
List of references (1) Grunbaum, Z., et al., J.Nucl.Med., 1987,28:68-75.
(2)Mannan，R.H.，et?al.，J.Nucl.Med.，1991，32：1764-1770.
(3)Ballinger，J.R.，et?al.，J.Nucl.Med.，1996，37：1023-1031.
The Unit Weight radioactivity ratio of the stripped tumor of Fig. 5 and each internal organs, tissue
Embodiment
The present invention will have the aromatic compound of nitro earlier according to conventional method cyano groupization, then this intermediate product again with azanol reaction, generate corresponding amino oxime part, also can utilize synthetic aromatic series amino oxime (Eloy, E., the et al. that has nitro of other method, Chem.Rev., 1962,62:155), use it then as the precursor preparation tissue anoxia developing agent.
The preparation of embodiment 11-amino-3-(2-nitroimidazole) propionaldoxime (Compound I)
In the 5ml triethylamine, add 420mg 2-nitroimidazole, constantly stir, behind the slow Dropwise 5 .0ml acrylonitrile, N
2Gas shiled refluxed 6 hours.The pressure reducing and steaming solvent.Add a small amount of distilled water, filter, collect orange-yellow insoluble matter.In filtrate, add chloroform (CHCl
3) 4 * 25mL, extraction merges organic facies, adds anhydrous sodium sulfate (Na
2SO
4) drying, evaporated under reduced pressure is collected orange-yellow powder, and merges with orange-yellow insoluble matter.With CHCl
3Recrystallization obtains the orange-yellow crystal of 300mg, productive rate 48%.With the deuterochloroform is solvent,
1The H chemical shift of NMR is: 3.04 (triplet, 2H, CH
2), 4.70 (triplet, 2H, CH
2), 7.24 (unimodal, 1H, imidazole radicals H), 7.27 (unimodal, 1H, imidazole radicals H).This crystal is 1-β-cyanoethyl-2-nitroimidazole.
In 10ml methanol, add 40mg 1-β-cyanoethyl-2-nitroimidazole, the methanol solution of the azanol of 1.2mmol, N
2Gas shiled refluxed 18 hours.The pressure reducing and steaming solvent.With the ethyl acetate is eluent, and silicagel column separates.The pressure reducing and steaming solvent, dehydrated alcohol/petroleum ether recrystallization obtains light yellow crystal 22mg, productive rate 46%.Fusing point: 118-119 ℃.With the deuterated dimethyl sulfoxide is solvent,
1The H chemical shift of NMR is: 2.50 (triplet, 2H, CH
2), 4.56 (triplet, 2H, CH
2), 5.49 (unimodal, 2H, NH
2), 7.15 (unimodal, 1H, imidazole radicals H), 7.56 (unimodal, 1H, imidazole radicals H), 8.94 (unimodal, 1H OH), in addition, does not detect other peak.This crystal is 1-amino-3-(2-nitroimidazole) propionaldoxime (Compound I).
The preparation of embodiment 21-amino-3-(4-nitroimidazole) propionaldoxime (Compound I I)
In the 25ml triethylamine, add 2.5g 4-nitroimidazole, constantly stir, slowly drip the 25ml acrylonitrile after, N
2Gas shiled refluxed 4 hours.The pressure reducing and steaming solvent.Add a small amount of distilled water, filter, collect white crystalline thing.With the absolute methanol recrystallization, obtain the 3.1g clear crystal, productive rate 84%.With the deuterated dimethyl sulfoxide is solvent,
1The H chemical shift of NMR is: 3.17 (triplet, 2H, CH
2), 4.39 (triplet, 2H, CH
2), 7.93 (unimodal, 1H, imidazole radicals H), 8.47 (unimodal, 1H, imidazole radicals H).This crystal is 1-β-cyanoethyl-4-nitroimidazole.
In 10ml methanol, add 1.7g 1-β-cyanoethyl 4-nitroimidazole, the methanol solution of the azanol of 20mmol, N
2Gas shiled refluxed 20 hours.The pressure reducing and steaming solvent.With the ethyl acetate is eluent, and silicagel column separates.The pressure reducing and steaming solvent, absolute methanol/petroleum ether recrystallization obtains clear crystal 0.76g, productive rate 38%.Fusing point: 128.5-130 ℃.With the deuterated acetone is solvent,
1The H chemical shift of NMR is: 2.62 (triplet, 2H, CH
2), 4.36 (triplet, 2H, CH
2), 5.21 (unimodal, 2H, NH
2), 7.63 (unimodal, 1H, imidazole radicals H), 8.11 (unimodal, 1H, imidazole radicals H), 8.38 (unimodal, 1H OH), in addition, does not detect other peak.This crystal is 1-amino-3-(4-nitroimidazole) propionaldoxime (Compound I I).
The radioactivity of embodiment 3 Compound I, II
99mThe Tc labelling
The 1ml phosphate buffer (pH=7.4,0.1mol/l), 5 μ g sodium tartrates, 50 μ g Compound I or II, 5 μ g stannous chloride (SnCl
2.2H
2O), 100 μ l TcO
4 -Leacheate, 75 ℃ of heating in water bath 30 minutes.Mark rate is greater than 90%.
Male Kunming white mice, body weight 20-25g transplants to its left oxter
S180Sarcoma experimentized after one week.With marking fluid 0.1ml (radioactive intensity 40 μ Ci), in the mice body,, respectively the white mice eye socket is got blood by tail vein injection at different time, disconnected neck is put to death, and takes out each internal organs and tissue, washes with water, wipes away to weigh after doing and use
NaI (TI)Well type probe is surveyed its radioactive intensity, and each time point is parallel does 5 white mice, gets its meansigma methods, the results are shown in Figure 5.
Claims (5)
1. a tissue anoxia developing agent is characterized in that it comprises the amino oxime part of nitryl aromatic, goes back the technetium-99m of ortho states, and the coordination structure of this part and technetium-99m formation, has following structural formula:
Wherein, R represents the nitryl aromatic group; R ' is C
0～C
8Alkylidene, or cycloalkylidene, or alkenylene, or alkynylene, perhaps their substituent; R " be H, or alkyl, perhaps substituted alkyl.
2. the precursor of a tissue anoxia developing agent, its structure is:
Wherein, R represents the nitryl aromatic group; R ' is C
0～C
8Alkylidene, or cycloalkylidene, or alkenylene, or alkynylene, perhaps their substituent; R " be H, or alkyl, perhaps substituted alkyl.
3. the precursor of tissue anoxia developing agent as claimed in claim 2 is characterized in that R ' represents ethylene group.
4. the precursor of tissue anoxia developing agent as claimed in claim 2 is characterized in that R is nitroimidazole or the nitroimidazole that is substituted.
5. the precursor of tissue anoxia developing agent as claimed in claim 4 is characterized in that R is 2-nitroimidazole or 4-nitroimidazole.
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| CN 01110037 CN1131071C (en) | 2001-03-27 | 2001-03-27 | Tissue anoxia developing agent and its precursor |
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| CN1318095C (en) * | 2003-11-27 | 2007-05-30 | 上海市胸科医院 | Tracer agent for oxygen lacking tumor cell and its usage |
| CN101721720B (en) * | 2008-10-29 | 2011-08-24 | 阮建评 | Nitroimidazole-amino acid compound nuclide hypoxic contrast agent and precursor thereof |
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