CN105198930A - Bipyridine tricarbonyl technetium-99m-marked long-chain fatty acid derivative and application thereof - Google Patents

Bipyridine tricarbonyl technetium-99m-marked long-chain fatty acid derivative and application thereof Download PDF

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CN105198930A
CN105198930A CN201510571327.9A CN201510571327A CN105198930A CN 105198930 A CN105198930 A CN 105198930A CN 201510571327 A CN201510571327 A CN 201510571327A CN 105198930 A CN105198930 A CN 105198930A
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fatty acid
chain fatty
acid derivative
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CN105198930B (en
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张华北
薛倩倩
刘建萍
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Beijing Normal University
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Abstract

The invention relates to a bipyridine tricarbonyl technetium-99m-marked long-chain fatty acid derivative and application thereof. The long-chain fatty acid derivative is mainly used as a myocardial imaging agent. According to the long-chain fatty acid derivative, the liver background is lowered mainly through reasonably improving a molecular structure to reduce the lipid solubility of a compound, unsaturated aromatic rings are introduced in long-chain fatty acid, and the beta-oxidation of the fatty acid can be blocked, the myocardial uptake is improved and myocardial retention is prolonged, so as to provide a novel tricarbonyl technetium-99m-marked long-chain fatty acid derivative possibly applied to clinic. Moreover, the marking percentage of the technetium-99m-marked long-chain fatty acid derivative is high, and clinical application feasibility and operability are provided.

Description

The long-chain fatty acid derivative that bipyridines three carbonyl is technetium-99 m labeled and application thereof
Technical field
The present invention relates to the class long chain fatty acid compounds in organic chemistry, medicinal chemistry art, relate to the technetium-99 m labeled long-chain fatty acid derivative of a kind of novel bipyridines three carbonyl and application thereof particularly.
Background technology
Cardiovascular disorder, also known as circulation system disease, comprises coronary heart disease, cerebrovascular disease, rheumatic heart disease, congenital heart disease etc.World Health Organization's global disease burden in 2004 report is pointed out, cardiovascular disorder is global number one killer, and within 2004, the whole world has 1,700 ten thousand people to die from cardiovascular disorder, and before the year two thousand thirty, death toll is estimated more than 23,000,000 [1].This disease originates from the recycle system pathology of human body, but general all closely related with arteriosclerosis, and arteriosclerosis is because arteries inwall has fat, the depositions such as cholesterol, the formation of fibrous tissue and calcification and the pathology that produces.This pathological development then forms coronary heart disease to during heart coronary artery.From natural arterial to asymptomatic atherosclerosis, arterial pulse pipe is narrow, needs the time of more than ten years to decades, but from asymptomatic arteriosclerosis to Symptomatic arteriosclerosis, as coronary heart disease or apoplexy, only needs several minutes.Therefore early diagnosis cardiovascular and cerebrovascular diseases is the key reducing this sick mortality ratio.Radiopharmaceuticals has vital role in the early diagnosis of cardiovascular disorder.
PET/SPECT imaging technique is considered to the optimal path realizing cardiovascular disorder early diagnosis at present.Up to now, existing developer comprises: myocardial perfusion imaging agent, myocardium agent, myocardial infarction developer, myocardial metabolic agent, cardiac muscle nerve and receptor developer etc., myocardial metabolic agent is significant for the metabolism and function status studying cardiac muscular tissue.
Lipid acid and glucose pass through oxygenizement, the energy produced forms the main energy supply material of ATP as cardiac muscle, patient's myocardial ischaemia, heart failure etc. can be judged according to its metabolic condition in cardiac muscle, therefore lipid acid and glucose myocardial metabolic agent can be used for studying myocardium metabolism and function, and they have critical role in the research of nuclear cardiology.In cardiac muscle, the acetyl-CoA of 50%-70% is from the β-oxidation of lipid acid, and therefore the oxidation of Myocardial Fatty Acids is for diagnosis amyocardia, and in heart failure and myocardial ischaemia etc. are significant. 99mthe myocardial metabolic agent of Tc mark can be used to myocardial ischemia location, and reaction myocardial metabolism changes of function, detects the situation etc. of myocyte survival, then for clinical diagnosis cardiovascular disorder provides reliable foundation.
The main metabolize imaging agent used has clinically at present 18f-FDG, 11the PET developer of C-palmitate, 123i-IPPA and 123the SPECT video picture of I-BMIPP.But there is no and be applied to clinical nucleic good properties and the metabolize imaging agent of cheap Tc-99m mark.
At present, studies in China 99mthe myocardial metabolic agent of Tc mark is fewer, and study in the world 99mthe myocardial metabolic agent of Tc mark achieves higher heart uptake.The eighties has been applied to clinical diagnosis 99mtc-MIBI myocardial perfusion imaging has certain accuracy to diagnosis of myocardial ischemia and necrosis, but it exists an obvious weak point in Clinical practice process, due to 99mtc-MIBI is main in vivo to discharge through liver metabolism, when carrying out myocardial imaging after injection 1-2 hour, in liver, radioactive delay usually affects myocardial imaging, therefore need patient to take fat meal one in checking process after injection video picture half an hour and promote that in liver, medicine is got rid of, and reduce liver radioactivity, remove its impact on cardiac muscle, this is inconvenient for a part of patient.2004, YasuhiroMagata etc. [10]synthesized the series fatty acid compound that MAMATc-99m core coordinates, results of animal shows that series fatty acid compound that Tc-99m marks has higher myocardium initial ingest and myocardial clearance fast, within 2min [ 99mtc] the MAMA-HDA heart/blood ratio is 3.6, is β-oxidation metabolism through myocardial metabolism analysis, therefore [ 99mtc] MAMA-HAD is a potential longer chain fatty acid myocardial metabolic agent.
2006, Beijing Normal University Wang Xue is refined waited people [11]with short chain diacid and MAMA part for starting raw material, synthesized a series of Tc-99m core mark long-chain fatty acid derivative [ 99mtc]-MAMA-(CH2) ncOOH (n=14,15,16,17).The Biodistribution data display of normal mouse, during 5min, the picked-up percentage ratio of this kind of marker in cardiac muscle is followed successively by 5.73.5.52.4.82.4.03, but higher and serum at the bottom of principal is except comparatively slow, and the heart/blood value is low.
2007, YasushiArano [12]etc. reported first with [ 99mtc] CpTT-PA carries out the mensuration of myocardial fatty acid metabolic, result shows: in 1min, ID/g reaches 4.60 up to painstaking effort ratio in 3.85%, 10min, myocardial metabolism experiment display 67% enter into heart [ 99mtc] CpTT-PA absorbed, [ 99mtc] CpTT-propionicacid is through the final product after 6 beta-oxidation.2008, YearnSeongChoe [13]deng [ 99mtc] CpTT-PA architecture basics on remain the carbonyl be connected with pentadiene ring, synthesized compound [ 99mtc] CpTT-16-oxo-HAD.Results of animal shows: in 1min, ID/g is up to 9.03%, higher than the former, but its liver background increases a lot, affects myocardial imaging, and the metabolisable form of the two is identical.
As can be seen from data in literature, 99mthe advantage of lipid acid myocardial metabolic agent of Tc mark has higher myocardium initial ingest and myocardial metabolism fast, but its shortcoming is that the metabolism in liver is slower, form higher liver background and affect imaging results, in the myocardial metabolic agent that therefore Technetium marks, also have very large research space.
Summary of the invention
The object of this invention is to provide the technetium-99 m labeled long-chain fatty acid derivative of a kind of novel bipyridines three carbonyl and application thereof, this invention is intended to solve at present 99mthe shortcoming that when derivative of fatty acid of Tc mark is applied to myocardial metabolic agent, liver background is high, by rationally improving molecular structure to reduce the fat-soluble of compound, thus reduce liver background, unsaturated aromatic nucleus is introduced in longer chain fatty acid, the β-oxidation of lipid acid can be hindered, improve heart uptake, extend cardiac muscle and be detained, thus provide and a kind ofly may be applied to the technetium-99 m labeled long-chain fatty acid derivative of clinical novel three carbonyls.The object of the invention is to be achieved through the following technical solutions:
The long-chain fatty acid derivative that novel bipyridines three carbonyl is technetium-99 m labeled, the general formula of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is
Wherein A is-CH 2or e is-CH 2or
N a, n bbe positive integer, n afor 1-16, n bbe 0 or 1,
Further, n bwhen being 0, A is-CH 2, E is-CH 2or n afor the positive integer of 4-12, namely the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is chemical compounds I or II, and chemical compounds I and II is shown below:
(n apositive integer for 4-12);
Preferably, the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is:
Further, n bwhen being 0, A is-CH 2, E is n afor the positive integer of 4-12; Preferably, the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is wherein n is 8-16.
Further, n bwhen being 1, R is S, O or N, and A is-CH 2or e is-CH 2or n afor the positive integer of 1-16.
Further, n bwhen being 1, R is S, O or N, and A is-CH 2or e is-CH 2or n ait is the positive integer of 1 or 8-14.
Further, N aand n bwhen being 1, R is O or N, A is-CH 2or e is-CH 2or preferably, the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is:
Further, n bwhen being 1, R is S, O or N, and A is-CH 2or e is-CH 2or n afor the positive integer of 8-14.
Further, the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is: wherein A is-CH 2or e is-CH 2or n afor 8-14.
Further, n bbe 1, n afor the positive integer of 8-14, R is S, O or N, and A is time, E is-CH 2or n bbe 1, n afor the positive integer of 8-14, R is S, O or N, and A is-CH 2time, E is-CH 2.
Further, the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is:
An application for the long-chain fatty acid derivative that described novel bipyridines three carbonyl is technetium-99 m labeled, the technetium-99 m labeled long-chain fatty acid derivative of this bipyridines three carbonyl is applied as myocardial developer.
The invention provides the technetium-99 m labeled long-chain fatty acid derivative of a kind of novel bipyridines three carbonyl and application thereof, its beneficial effect mainly had: effectively reduce liver background, marked by fac-[99mTc (CO) 3 (H2O) 3]+intermediate, improve mark rate, provide feasibility and the operability of clinical application.
Accompanying drawing explanation
With reference to the accompanying drawings the present invention is described in further detail below.
Fig. 1 is the compound III described in the embodiment of the present invention 5 1hNMR;
Fig. 2 is the compounds Ⅳ described in the embodiment of the present invention 5 1hNMR;
Fig. 3 is the compounds Ⅳ described in the embodiment of the present invention 5 13cNMR;
Fig. 4 is the MS of the compounds Ⅳ described in the embodiment of the present invention 5;
Fig. 5 is compound V a described in the embodiment of the present invention 5 1hNMR;
Fig. 6 is compound V a described in the embodiment of the present invention 5 13cNMR;
Fig. 7 is the MS of compound V a described in the embodiment of the present invention 5;
Fig. 8 be intermediate described in the embodiment of the present invention 3 [ 99mtc (CO) 3(H 2o) 3] +the HPLC of intermediate;
Fig. 9 is the redio-HPLC of the compound V described in the embodiment of the present invention 5;
Figure 10 is the compound III described in the embodiment of the present invention 6 1hNMR;
Figure 11 is the compounds Ⅳ described in the embodiment of the present invention 6 1hNMR;
Figure 12 is the compounds Ⅳ described in the embodiment of the present invention 6 13cNMR;
Figure 13 is the compound V described in the embodiment of the present invention 8 1hNMR;
Figure 14 is the compound V described in the embodiment of the present invention 8 13cNMR;
Figure 15 is the MS of the compound V described in the embodiment of the present invention 8;
Figure 16 is compound VI a described in the embodiment of the present invention 8 1hNMR.
Embodiment
As illustrated in figs. 1-16, the long-chain fatty acid derivative that a kind of novel bipyridines three carbonyl described in the embodiment of the present invention is technetium-99 m labeled and application thereof.For specific experiment case, embodiment is described below, should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Embodiment 1
The general structure of the long-chain fatty acid derivative that described novel bipyridines three carbonyl is technetium-99 m labeled is:
Wherein A is-CH 2or e is-CH 2or n a, n bbe positive integer, n afor 1-16, n bbe 0 or 1, and work as n bwhen being 1, R is S, O or N.
As further preferred embodiment, n bbe 0, A be-CH 2, E is-CH 2or time, the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is: wherein, n afor the positive integer of 4-12;
As further preferred embodiment, the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is: wherein, n afor the positive integer of 4-12;
As further preferred embodiment, n bwhen being 1, R is S, O or N, and A is-CH 2or e is-CH 2or n afor the positive integer of 1-16.
As further preferred embodiment, n bwhen being 1, R is S, O or N, and A is-CH 2or e is-CH 2or n ait is the positive integer of 1 or 8-14.
As further preferred embodiment, N aand n bwhen being 1, R is O or N, A is-CH 2or e is-CH 2or still more preferably, the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is:
As further preferred embodiment, n bwhen being 1, R is S, O or N, and A is-CH 2or e is-CH 2or n afor the positive integer of 8-14.
As further preferred embodiment, the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is: wherein A is-CH 2or e is-CH 2or n afor 8-14.
As further preferred embodiment, n bbe 1, n afor the positive integer of 8-14, R is S, O or N, and A is time, E is-CH 2or n bbe 1, n afor the positive integer of 8-14, R is S, O or N, and A is-CH 2time, E is-CH 2.More preferably, the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is: wherein, n2 is 8 ~ 14.
Embodiment 2: the synthetic route of following compounds is:
1, wherein n 1for 8-16, R are S, O or N;
2, wherein n 2for 8-14, R are S, O or N;
3, wherein n 2for 8-14, R are S, O or N;
4, wherein n 2for 8-14, R are S, O or N;
Embodiment 3 ~ 13 is for choosing a compound in embodiment 2 in every compounds representatively, according to the synthetic route in embodiment 2 in detail its concrete synthesis step is described in detail, and the synthesis step of other similar compounds is consistent with following detailed process, do not repeating one by one to write exactly here.
Embodiment 3: the preparation of marker intermediate
Fac-[ 99mtc (CO) 3(H 2o) 3] +the preparation of intermediate: get 5mgNa2CO3,10mgNaBH4,15mg Seignette salt in 10mL penicillin bottle, add 1ml physiological saline wherein, fully shake up, vacuumize with the disposable needle tubing of 10ml, gas 15min in logical carbon monoxide, air in emptying bottle, then injects 2mlNa 99mtcO 4elutriant (about 13mci), 80 DEG C of oil bath continuous heating 30min (reaction process one leads directly to CO (carbon monoxide converter) gas), cooling, obtain intermediate [ 99mtc (CO) 3(H 2o) 3] +, stand-by, this Intermediates Intermediate [ 99mtc (CO) 3(H 2o) 3] +hPLC figure as shown in Figure 8.
Intermediate [the NEt of the title complex of synthesis rhenium 4] 2[Re (CO) 3br 3] preparation: under nitrogen protection, take 505.4mg (1.2mmol) bromination tetraethyl-amine and 415.2mg (1.0mmol) bromination pentacarbonyl closes rhenium, add diethylene glycol dimethyl ether solvent 100ml, first 80 DEG C are slowly heated under magnetic agitation, stir and treat that solid dissolves completely in a moment, be warming up to 120 DEG C of reactions again to spend the night, faint yellow solid is had to produce in solution, filtered while hot solid, then with cold diethylene glycol dimethyl ether and anhydrous diethyl ether washing several, be placed in vacuum drier dry, dried pressed powder uses a small amount of absolute ethanol washing again, filter, vacuum-drying obtains product [NEt 4] 2[Re (CO) 3br 3].Obtain light yellow solid product 680mg, productive rate 86.7%, fusing point 302.9-305.4, not repurity, be directly used in next step reaction.
It should be noted that: all radioactive compounds determine its structure according to the title complex of its non-radioactive analogs rhenium.Because the element technetium marked in compound does not have corresponding stable technetium compound to determine structure and the appearance time of radioactive technetium, therefore, have selected element rhenium (Re) tagged compound similar to element technetium character to determine the structure of the compound of mtc labeled.
Embodiment 4: preparation
1. under condition of ice bath by the SOCl of 30ml 2dropwise join in the dodecanedioic acid of 4.60g, continue to stir half an hour, the oil bath condition of 90 DEG C flows through night next time, removes unnecessary SOCl 2, obtain transparent oil product, be compound ii, be not further purified, give over to next step and use.
2. to step 1. in gained compound ii in add the anhydrous methanol of 5ml, stir 2h at 60 DEG C, obtain the mixture that primary product is III, do not deal with, give over to next step and use.
3. two for 4.0g (2-pyridylmethyl) amine is dissolved in dry dichloromethane solution, under ice bath, and be dropwise added drop-wise in the compound III of step 2. gained, stir half an hour, add the methylene dichloride being dissolved with 2.8g aluminum trichloride (anhydrous) again, stirring at room temperature 5h, then process with the hydrochloric acid of 1mol/L, dichloromethane extraction five times, anhydrous magnesium sulfate drying, carry out silica gel column chromatography with petrol ether/ethyl acetate=8/3 (adding centesimal triethylamine solution), obtain compounds Ⅳ, three step comprehensive yieds are 34.6%.
4. by the [NEt of 140mg (0.17mmol) 4] 2[Re (CO) 3br 3] be dissolved in 10ml anhydrous methanol, compounds Ⅳ 72.25mg (0.17mmol) is dissolved in 6ml anhydrous methanol, and be slowly added drop-wise in above-mentioned solution, stirring at room temperature 4h, (TLC monitoring) reacts complete, rotary evaporation is except desolventizing, add the potassium hydroxide solution 2ml of the 1M now joined again, 6ml anhydrous methanol, 80 DEG C of reaction 1h hydrolysis, react complete, neutralize with the hydrochloric acid soln of 2M, until solution is in acid, be spin-dried for, use a small amount of dissolve with methanol, filter insolubles, with methylene dichloride: methyl alcohol=15:1 (adding the triethylamine of 1% and the glacial acetic acid of 0.5%) for developping agent carries out being separated to obtain final product, be compound V a of rhenium mark, productive rate 45.6%.
5. compounds Ⅳ is made into the aqueous solution of 1mg/ml, add that 1ml (about 2-3mci) prepares wherein [ 99mtc (CO) 3(H 2o) 3] +intermediate, adjust PH ≈ 8 with hydrochloric acid, 30min is reacted in the oil bath being placed in 80 DEG C, and then adds the NaOH solution reaction 30min of 1ml0.8M, reflect complete, adjust PH to acid with the HCl of 1M, underpressure distillation, is dissolved in proper amount of methanol, filter, concentrated, obtain target product V, productive rate is 68.2%.
Embodiment 5: preparation
1. 13.97g (0.05mol) 12-bromo-dodecane is acid-soluble in the methylene dichloride of 200ml drying, add 6 DMF catalysis and add 6ml oxalyl chloride again, stirring at room temperature 4 hours, rotary evaporation, removing methylene dichloride and excessive oxalyl chloride, obtain compound ii, do not deal with, be directly used in next step reaction.
2. in the compound ii of gained in 1., add the methylene dichloride of 70ml drying, under ice-water bath condition, slow dropping 7.44g (0.05mol) is dissolved in the thiophene methyl propionate in 40ml dichloromethane solution, dropwise after 1h, stir about 30min, under ice-water bath condition, add 6.68g aluminum trichloride (anhydrous), naturally heat up, stirring is spent the night in batches.TLC monitors, after having reacted, under ice bath, with the hydrochloric acid of 1mol/L, use methylene dichloride (3*50ml) to extract again, merge lower floor's organic solution, use appropriate anhydrous magnesium sulfate drying, filter, desolventizing is revolved in decompression, and crude product silica column purification (sherwood oil: ethyl acetate=10:1 ~ 8:1), obtains 14.0g yellow solid matter, be compound III, three step comprehensive yieds 67.3%; Compound III 1hNMR figure as shown in Figure 1.
3. by two for 843.75mg (4.2mmol) (2-pyridylmethyl) amine, DIEA1.5ml (8.4mmol) and KI69mg (0.42mmol) is dissolved in 40ml acetonitrile, adding 1.5g (3.6mmol) compound III wherein, under nitrogen protection, stir 2 hours under 70 degrees Celsius, it is made fully to mix, be warmed up to 85 degrees Celsius again, backflow is spent the night, TLC monitors, react complete and revolve excess acetonitrile, use saturated sodium carbonate solution respectively, water, saturated common salt is washed, with dichloromethane extraction, merge organic layer, anhydrous magnesium sulfate drying, filter, spin off methylene dichloride, crude product crosses silica column purification, (adding the sherwood oil of 1% triethylamine: ethyl acetate=8:3 solution is developping agent), 1.3g yellow oily pure compound, be compounds Ⅳ, productive rate 67.4%.Compounds Ⅳ 1hNMR, 13cNMR, MS spectrogram respectively as shown in Figure 2,3, 4.
4. reaction process with the step in embodiment 4 4., obtains target product V a, productive rate 54.3%, target product V a's 1hNMR, 13cNMR, MS spectrogram is respectively as shown in Fig. 5,6,7.
5. reaction process with the step in embodiment 4 5., obtains target product V, and productive rate is 70.5%, and the redio-HPLC spectrogram of this target product V as shown in Figure 9.
The structure of this target product V can be determined by above collection of illustrative plates.
Embodiment 6: preparation
1. 13.37g (0.05mol) 11-bromo-n-11 is acid-soluble in the methylene dichloride of 200ml drying, add 6 DMF catalysis and add 6ml oxalyl chloride again, stirring at room temperature 4 hours, rotary evaporation, removing methylene dichloride and excessive oxalyl chloride, obtain compound ii, do not deal with, be directly used in next step reaction.
2. in step 1. middle gained compound ii, add the methylene dichloride of 70ml drying, under ice-water bath condition, slow dropping 8.40g (0.05mol) is dissolved in the furanpropionic acid ethyl ester in 40ml dichloromethane solution, dropwise after 1h, stir about 30min, under ice-water bath condition, add 6.68g aluminum trichloride (anhydrous), naturally heat up, stirring is spent the night in batches.TLC monitors, after having reacted, under ice bath, with the hydrochloric acid of 1mol/L, then use methylene dichloride (3*50ml) to extract, merge lower floor's organic solution, use appropriate anhydrous magnesium sulfate drying, filter, decompression revolves desolventizing, crude product silica column purification (sherwood oil: ethyl acetate=10:1 ~ 8:1), obtain 14.0g yellow solid matter, be compound III, two step comprehensive yieds 67.3%, the 1HNMR spectrogram of this compound III as shown in Figure 10;
3. by two for 843.75mg (4.2mmol) (2-pyridylmethyl) amine, DIEA1.5ml (8.4mmol) and KI69mg (0.42mmol) is dissolved in 40ml acetonitrile, adding 1.5g (3.6mmol) compound III wherein, under nitrogen protection, stir 2 hours under 70 degrees Celsius, it is made fully to mix, be warmed up to 85 degrees Celsius again, backflow is spent the night, TLC monitors, react complete and revolve excess acetonitrile, use saturated sodium carbonate solution (2*30ml) respectively, water (2*30ml), saturated aqueous common salt (2*30ml) is washed, extract with methylene dichloride (3*30ml), merge organic layer, anhydrous magnesium sulfate drying, filter, spin off methylene dichloride, crude product crosses silica column purification, (adding the sherwood oil of 1% triethylamine: ethyl acetate=8:3 solution is developping agent), 1.25g yellow oily pure compound, be compounds Ⅳ, productive rate 63.5%, this compounds Ⅳ 1hNMR, 13cNMR spectrogram as shown in figure 11.
4. reaction process with the step in embodiment 4 4., obtains target product V a, and productive rate is 48.6%.
5. reaction process with the step in embodiment 4 5., obtains target product V, and productive rate is 78.3%.
Embodiment 7: preparation
1. by acid-soluble in the methylene dichloride of 200ml drying for 13.97g (0.05mol) 12-bromo-dodecane, add 6 DMF catalysis and add 6ml oxalyl chloride again, stirring at room temperature 4 hours, rotary evaporation, removing methylene dichloride and excessive oxalyl chloride, be compound ii, do not deal with, be directly used in next step reaction.
2. in gained compound ii in 1., add the methylene dichloride of 70ml drying, under ice-water bath condition, slow dropping 8.40g (0.05mol) is dissolved in the pyrrole propanoic acid methyl esters in 40ml dichloromethane solution, dropwise after 1h, stir about 30min, under ice-water bath condition, add 6.68g aluminum trichloride (anhydrous), naturally heat up, stirring is spent the night in batches.TLC monitors, after having reacted, under ice bath, with the hydrochloric acid of 1mol/L, methylene dichloride (3*50ml) is used to extract again, merge lower floor's organic solution, use appropriate anhydrous magnesium sulfate drying, filter, desolventizing is revolved in decompression, crude product silica column purification (sherwood oil: ethyl acetate=10:1 ~ 8:1), obtains 14.0g yellow solid matter, two step comprehensive yieds 67.3%;
3. by two for 843.75mg (4.2mmol) (2-pyridylmethyl) amine, DIEA1.5ml (8.4mmol) and KI69mg (0.42mmol) is dissolved in 40ml acetonitrile, adding 1.5g (3.6mmol) compound III wherein, under nitrogen protection, stir 2 hours under 70 degrees Celsius, it is made fully to mix, be warmed up to 85 degrees Celsius again, backflow is spent the night, TLC monitors, react complete and revolve excess acetonitrile, use saturated sodium carbonate solution (2*30) respectively, water (2*30), saturated aqueous common salt (2*30) is washed, extract with methylene dichloride (3*30), merge organic layer, anhydrous magnesium sulfate drying, filter, spin off methylene dichloride, crude product crosses silica column purification, (adding the sherwood oil of 1% triethylamine: ethyl acetate=8:3 solution is developping agent), 0.7g yellow oily pure compound, productive rate 36.5%,
4. reaction process with the step in embodiment 4 4., obtains target product V a, productive rate 46.8%.
5. reaction process with the step in embodiment 4 5., obtains target product V, and productive rate is 75.6%.
Embodiment 8: preparation
1. 13.97g (0.05mol) 12-bromo-dodecane is acid-soluble in the methylene dichloride of 200ml drying, add 6 DMF catalysis and add 6ml oxalyl chloride again, stirring at room temperature 4 hours, rotary evaporation, removing methylene dichloride and excessive oxalyl chloride, obtain compound ii, do not deal with, be directly used in next step reaction.
2. to step 1. in gained acyl chlorides add the methylene dichloride of 70ml drying, under ice-water bath condition, slow dropping 7.44g (0.05mol) is dissolved in the thiophene methyl propionate in 40ml dichloromethane solution, dropwise after 1h, stir about 30min, under ice-water bath condition, add 6.68g aluminum trichloride (anhydrous), naturally heat up, stirring is spent the night in batches.TLC monitors, after having reacted, under ice bath, with the hydrochloric acid of 1mol/L, use methylene dichloride (3*50ml) to extract again, merge lower floor's organic solution, use appropriate anhydrous magnesium sulfate drying, filter, desolventizing is revolved in decompression, and crude product silica column purification (sherwood oil: ethyl acetate=10:1-8:1), obtains 14.0g yellow solid matter, be compound III, two step comprehensive yieds 67.3%;
3. by two for 843.75mg (4.2mmol) (2-pyridylmethyl) amine, DIEA1.5ml (8.4mmol), KI69mg (0.42mmol) is dissolved in 40ml acetonitrile, adding 1.5g (3.6mmol) compound III wherein, under nitrogen protection, stir 2 hours under 70 degrees Celsius, it is made fully to mix, be warmed up to 85 degrees Celsius again, backflow is spent the night, TLC monitors, react complete and revolve excess acetonitrile, use saturated sodium carbonate solution (2*30) respectively, water (2*30), saturated aqueous common salt (2*30) is washed, extract with methylene dichloride (3*30), merge organic layer, anhydrous magnesium sulfate drying, filter, spin off methylene dichloride, crude product crosses silica column purification, (adding the sherwood oil of 1% triethylamine: ethyl acetate=8:3 solution is developping agent), 1.3g yellow oily pure compound, be compounds Ⅳ, productive rate 67.4%.
4. 1.54g (2.8mmol) compounds Ⅳ is dissolved in the mixed solution of 15ml trifluoroacetic acid and 15ml methylene dichloride, 745g sodium borohydride is added in batches, stirring at room temperature 5h, TLC monitors (product point is slightly higher than raw material point), react complete, with dchloromethane, ph=10 is adjusted with the sodium hydroxide solution of 1M, with dichloromethane extraction, crude product sherwood oil: ethyl acetate (adding the triethylamine of 1%)=3:1 is that silicagel column crossed by developping agent, obtain 0.56g pure compound V (pale yellowish oil compound), productive rate 37.3%, this compound V 1hNMR, 13cNMR, MS figure is respectively as shown in Figure 13 ~ 15.
5. reaction process with the step in embodiment 4 4., obtains target product VI a, productive rate 43.9%, this target product VI a's 1hNMR as shown in figure 16.
6. reaction process with the step in embodiment 4 5., obtains target product VI, and productive rate is 78.3%.
Embodiment 9: preparation
1. 13.97g (0.05mol) 12-bromo-dodecane is acid-soluble in the methylene dichloride of 200ml drying, add 6 DMF catalysis and add 6ml oxalyl chloride again, stirring at room temperature 4 hours, rotary evaporation, removing methylene dichloride and excessive oxalyl chloride, obtain compound ii, do not deal with, be directly used in next step reaction.
2. to step 1. in gained acyl chlorides add the methylene dichloride of 70ml drying, under ice-water bath condition, slow dropping 8.40g (0.05mol) is dissolved in the furanpropionic acid ethyl ester in 40ml dichloromethane solution, dropwise after 1h, stir about 30min, under ice-water bath condition, add 6.68g aluminum trichloride (anhydrous), naturally heat up, stirring is spent the night in batches.TLC monitors, after having reacted, under ice bath, with the hydrochloric acid of 1mol/L, use methylene dichloride (3*50ml) to extract again, merge lower floor's organic solution, use appropriate anhydrous magnesium sulfate drying, filter, desolventizing is revolved in decompression, and crude product silica column purification (sherwood oil: ethyl acetate=10:1 ~ 8:1), obtains 14.0g yellow solid matter, be compound III, two step comprehensive yieds 67.3%
3. by two for 843.75mg (4.2mmol) (2-pyridylmethyl) amine, DIEA1.5ml (8.4mmol), KI69mg (0.42mmol) is dissolved in 40ml acetonitrile, adding 1.5g (3.6mmol) compound III wherein, under nitrogen protection, stir 2 hours at 70 DEG C, it is made fully to mix, be warmed up to 85 degrees Celsius again, backflow is spent the night, TLC monitors, react complete underpressure distillation removing excess acetonitrile, use saturated sodium carbonate solution (2*30) respectively, water (2*30), saturated aqueous common salt (2*30) is washed, extract with methylene dichloride (3*30), merge organic layer, anhydrous magnesium sulfate drying, filter, spin off methylene dichloride, crude product crosses silica column purification, (adding the sherwood oil of 1% triethylamine: ethyl acetate=8:3 solution is developping agent), obtain 1.25g yellow oily pure compound, be compounds Ⅳ, productive rate 63.5%.
4. 1.52g (2.8mmol) compounds Ⅳ is dissolved in the mixed solution of 15ml trifluoroacetic acid and 15ml methylene dichloride, 745g sodium borohydride is added in batches, stirring at room temperature 5h, TLC monitors, react complete, with dchloromethane, ph=10 is adjusted with the sodium hydroxide solution of 1M, with dichloromethane extraction, crude product sherwood oil: ethyl acetate (adding the triethylamine of 1%)=3:1 is that silicagel column crossed by developping agent, obtain 0.58g pure compound (pale yellowish oil compound), be compound V, productive rate 37.9%.
5. reaction process with the step in embodiment 4 4., obtains target product VI a, productive rate 49.8%.
6. reaction process with the step in embodiment 4 5., obtains target product VI, and productive rate is 76.3%.
Embodiment 10: preparation
1. 13.97g (0.05mol) 12-bromo-dodecane is acid-soluble in the methylene dichloride of 200ml drying, add 6 DMF catalysis and add 6ml oxalyl chloride again, stirring at room temperature 4 hours, rotary evaporation, removing methylene dichloride and excessive oxalyl chloride, obtain compound ii, do not deal with, be directly used in next step reaction.
2. in step 1. middle gained compound ii, add the methylene dichloride of 70ml drying, under ice-water bath condition, slow dropping 8.40g (0.05mol) is dissolved in the pyrrole propanoic acid methyl esters in 40ml dichloromethane solution, dropwise after 1h, stir about 30min, under ice-water bath condition, add 6.68g aluminum trichloride (anhydrous), naturally heat up, stirring is spent the night in batches.TLC monitors, after having reacted, under ice bath, with the hydrochloric acid of 1mol/L, use methylene dichloride (3*50ml) to extract again, merge lower floor's organic solution, use appropriate anhydrous magnesium sulfate drying, filter, desolventizing is revolved in decompression, and crude product silica column purification (sherwood oil: ethyl acetate=10:1-8:1), obtains 14.0g yellow solid matter, be compound III, two step comprehensive yieds 67.3%
3. by two for 843.75mg (4.2mmol) (2-pyridylmethyl) amine, DIEA1.5ml (8.4mmol) and KI69mg (0.42mmol) is dissolved in 40ml acetonitrile, adding 1.5g (3.6mmol) compound III wherein, under nitrogen protection, stir 2 hours under 70 degrees Celsius, it is made fully to mix, be warmed up to 85 degrees Celsius again, backflow is spent the night, TLC monitors, react complete and revolve excess acetonitrile, use saturated sodium carbonate solution (2*30) respectively, water (2*30), saturated aqueous common salt (2*30) is washed, extract with methylene dichloride (3*30), merge organic layer, anhydrous magnesium sulfate drying, filter, spin off methylene dichloride, crude product crosses silica column purification, (adding the sherwood oil of 1% triethylamine: ethyl acetate=8:3 solution is developping agent), 0.7g yellow oily pure compound, be compounds Ⅳ, productive rate 36.5%.
4. 1.49g (2.8mmol) compounds Ⅳ is dissolved in the mixed solution of 15ml trifluoroacetic acid and 15ml methylene dichloride, 745g sodium borohydride is added in batches, stirring at room temperature 5h, TLC monitors, react complete, with dchloromethane, ph=10 is adjusted with the sodium hydroxide solution of 1M, with dichloromethane extraction, crude product sherwood oil: ethyl acetate (adding the triethylamine of 1%)=3:1 is that silicagel column crossed by developping agent, obtain 0.73g pure compound (pale yellowish oil compound), be compound V, productive rate 50.3%.
5. reaction process with the step in embodiment 4 4., obtains target product VI a, productive rate 47.9%.
6. with the step in 1 of the present embodiment 5., obtain target product VI, productive rate is 74.6% to reaction process.
Embodiment 11: preparation
1. under condition of ice bath by the SO of 30ml 2cl dropwise joins in the dodecanedioic acid (i.e. chemical compounds I) of 4.60g, continues to stir half an hour, refluxes stirred night, remove unnecessary SO under the oil bath condition of 90 DEG C 2cl, obtains transparent oil product, i.e. compound ii, does not do further process, gives over to next step and uses;
2. two for 4.0g (2-pyridylmethyl) amine is dissolved in dry dichloromethane solution, under ice bath, and be dropwise added drop-wise in the compound ii of step 1. gained, stir half an hour, add the methylene dichloride being dissolved with 2.8g aluminum trichloride (anhydrous) again, stirring at room temperature 5h, obtain compound III, be left intact, next step reaction can be directly used in;
3. 3.40g3-(2-thienyl)-methyl propionate is dissolved in the dichloromethane solution of 20ml, under condition of ice bath, dropwise add step 2. in the compound III that obtains, after half an hour, slowly add the aluminum trichloride (anhydrous) of 2.80g again, 5h is stirred under room temperature condition, under condition of ice bath, the hydrochloric acid soln of 1mol/l is slowly added in above-mentioned mixing solutions, until solution is in acid, and with dichloromethane extraction five times, anhydrous magnesium sulfate drying, silicagel column is crossed with petrol ether/ethyl acetate=8/3 (adding centesimal triethylamine solution), obtain compounds Ⅳ, three step comprehensive yieds are 32.6%.
4. reaction process with the step in embodiment 4 4., is compound V a of rhenium mark, productive rate 51.2%.
5. reaction process with the step in embodiment 4 5., obtains target product V, and productive rate is 68.4%.
Embodiment 12: preparation
1. under condition of ice bath by the SO of 30ml 2cl dropwise joins in the dodecanedioic acid (i.e. chemical compounds I) of 4.60g, continues to stir half an hour, refluxes stirred night, remove unnecessary SO under the oil bath condition of 90 DEG C 2cl, obtains transparent oil product, i.e. compound ii, does not do further process, gives over to next step and uses;
2. two for 4.0g (2-pyridylmethyl) amine is dissolved in dry dichloromethane solution, under ice bath, and be dropwise added drop-wise in the compound ii of step 1. gained, stir half an hour, add the methylene dichloride being dissolved with 2.8g aluminum trichloride (anhydrous) again, stirring at room temperature 5h, obtain compound III, be left intact, next step reaction can be directly used in.
3. 3.36g3-(2-furyl)-ethyl propionate is dissolved in the dichloromethane solution of 20ml, under condition of ice bath, dropwise join step 2. in the compound III that obtains, after half an hour, slowly add the aluminum trichloride (anhydrous) of 2.80g again, 5h is stirred under room temperature condition, under condition of ice bath, the hydrochloric acid soln of 1mol/l is slowly added in above-mentioned mixing solutions, until solution is in acid, and with dichloromethane extraction five times, anhydrous magnesium sulfate drying, silicagel column is crossed with petrol ether/ethyl acetate=8/3 (adding centesimal triethylamine solution), obtain compounds Ⅳ, three step comprehensive yieds are 40.2%.
4. reaction process with the step in embodiment 4 4., is compound V a of rhenium mark, productive rate 50.9%.
5. reaction process with the step in embodiment 4 5., obtains target product V, and productive rate is 65.8%.
Embodiment 13: preparation
1. under condition of ice bath by the SO of 30ml 2cl dropwise joins in the dodecanedioic acid (i.e. chemical compounds I) of 4.60g, continues to stir half an hour, refluxes stirred night, remove unnecessary SO under the oil bath condition of 90 DEG C 2cl, obtains transparent oil product, i.e. compound ii, does not do further process, gives over to next step and uses;
2. two for 4.0g (2-pyridylmethyl) amine is dissolved in dry dichloromethane solution, under ice bath, and be dropwise added drop-wise in the compound ii of step 1. gained, stir half an hour, add the methylene dichloride being dissolved with 2.8g aluminum trichloride (anhydrous) again, stirring at room temperature 5h, obtain product III, be left intact, next step reaction can be directly used in;
3. 3.06g3-(2-pyrryl)-methyl propionate is dissolved in the dichloromethane solution of 20ml, under condition of ice bath, dropwise join step 2. in the compound III that obtains, after half an hour, slowly add the aluminum trichloride (anhydrous) of 2.80g again, 5h is stirred under room temperature condition, under condition of ice bath, the hydrochloric acid soln of 1mol/l is slowly added in above-mentioned mixing solutions, until solution is in acid, and with dichloromethane extraction five times, anhydrous magnesium sulfate drying, silicagel column is crossed with petrol ether/ethyl acetate=8/3 (adding centesimal triethylamine solution), obtain compounds Ⅳ, three step comprehensive yieds are 33.2%.
4. reaction process with the step in embodiment 4 4., obtains target product V a, productive rate 48.5%.
5. reaction process with the step in embodiment 4 5., obtains target product V, and productive rate is 63.9%.
Embodiment: 14
For injected in mice embodiment 5 gained compound V, then the bio distribution result as shown in the table (%ID/g, n=5) of this compound in Mice Body.Compound V is
As seen from the above table, the bio distribution feature of this compound V is that heart uptake can reach 4.24 ± 0.93%ID/g after injectable drug 1min, presents quick wash-out during 1-5min, reaches 2.20 ± 0.35%ID/g when 5min; After 5min, elution speed is slack-off, has dropped to the 1.14%ID/g of 30min by the 2.205%ID/g of 5min; 30-120min elution speed is slower, and elution speed is comparatively slow on the whole, and anelasticity is better, illustrates and thiphene ring is introduced in technetium-99 m labeled longer chain fatty acid, serves the effect extending the residence time.In addition, this compound effectively reduces liver background, during 1min, liver picked-up is 7.79 ± 0.76%ID/g, liver picked-up is the highest appears at the rear 5min of injection, be 15.75 ± 2.28%ID/g, lower than the liver background of the current myocardial metabolic agent of report, illustrate that this compound likely becomes a potential myocardial metabolic agent.
The present invention is not limited to above-mentioned preferred forms, anyone for the present invention any modification done under enlightenment of the present invention or change, and every have the same or analogous technical scheme with the application, all drops within protection scope of the present invention.

Claims (10)

1. the long-chain fatty acid derivative that novel bipyridines three carbonyl is technetium-99 m labeled, is characterized in that: the general formula of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is
Wherein A is-CH 2or e is-CH 2or
N a, n bbe positive integer, n afor 1-16, n bbe 0 or 1.
2. the long-chain fatty acid derivative that novel bipyridines three carbonyl according to claim 1 is technetium-99 m labeled, is characterized in that: n bbe 0, A be-CH 2, E is-CH 2or time, the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is: wherein, n afor the positive integer of 4-12.
3. the long-chain fatty acid derivative that novel bipyridines three carbonyl according to claim 2 is technetium-99 m labeled, is characterized in that: the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is:
4. the long-chain fatty acid derivative that novel bipyridines three carbonyl according to claim 1 is technetium-99 m labeled, is characterized in that: n bwhen being 1, R is S, O or N.
5. the long-chain fatty acid derivative that novel bipyridines three carbonyl according to claim 4 is technetium-99 m labeled, is characterized in that: n bwhen being 1, R is S, O or N, n ait is the positive integer of 1 or 8-14.
6. the long-chain fatty acid derivative that novel bipyridines three carbonyl according to claim 5 is technetium-99 m labeled, is characterized in that: N aand n bwhen being 1, R is O or N.
7. the long-chain fatty acid derivative that novel bipyridines three carbonyl according to claim 5 is technetium-99 m labeled, is characterized in that: n afor the positive integer of 8-14.
8. the long-chain fatty acid derivative that novel bipyridines three carbonyl according to claim 7 is technetium-99 m labeled, is characterized in that: A is time, E is-CH 2or a is-CH 2time, E is-CH 2.
9. the long-chain fatty acid derivative that novel bipyridines three carbonyl according to claim 8 is technetium-99 m labeled, is characterized in that: the structure of the long-chain fatty acid derivative that described bipyridines three carbonyl is technetium-99 m labeled is:
10. the application of the long-chain fatty acid derivative that novel bipyridines three carbonyl according to any one in right 1 to 9 is technetium-99 m labeled, is characterized in that: the technetium-99 m labeled long-chain fatty acid derivative of this bipyridines three carbonyl is applied as myocardial developer.
CN201510571327.9A 2015-09-09 2015-09-09 The technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of bipyridines and its application Expired - Fee Related CN105198930B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102311459A (en) * 2011-06-03 2012-01-11 北京师范大学 Novel technetium-99m-labeled higher fatty acid derivative

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102311459A (en) * 2011-06-03 2012-01-11 北京师范大学 Novel technetium-99m-labeled higher fatty acid derivative

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Title
HUAHUI ZENG ET AL.: "Synthesis, characterization and biodistribution of new fatty acids conjugates bearing N,N,N-donors incorporated [99mTc/Re(CO)3]+", 《DALTON TRANS.》 *

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