CN105198930B - The technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of bipyridines and its application - Google Patents
The technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of bipyridines and its application Download PDFInfo
- Publication number
- CN105198930B CN105198930B CN201510571327.9A CN201510571327A CN105198930B CN 105198930 B CN105198930 B CN 105198930B CN 201510571327 A CN201510571327 A CN 201510571327A CN 105198930 B CN105198930 B CN 105198930B
- Authority
- CN
- China
- Prior art keywords
- chain fatty
- fatty acid
- technetium
- carbonyl
- long
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 C1CC*CC1 Chemical compound C1CC*CC1 0.000 description 8
- VRXALIIKPAZHHE-UHFFFAOYSA-N CN(Cc1ccccn1)Cc1ccccn1 Chemical compound CN(Cc1ccccn1)Cc1ccccn1 VRXALIIKPAZHHE-UHFFFAOYSA-N 0.000 description 1
- UBOXXEGSGUIRAJ-UHFFFAOYSA-N COC(CCc1ccc[nH]1)=O Chemical compound COC(CCc1ccc[nH]1)=O UBOXXEGSGUIRAJ-UHFFFAOYSA-N 0.000 description 1
- USTRJLXKHMURIF-UHFFFAOYSA-N COC(CCc1ccc[s]1)=O Chemical compound COC(CCc1ccc[s]1)=O USTRJLXKHMURIF-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to a kind of long-chain fatty acid derivatives of three carbonyl Tc 99m of bipyridines label and its application, the long-chain fatty acid derivative to be applied mainly as myocardial developer.It mainly reduces the fat-soluble of compound by rationally improving molecular structure, to reduce liver background, unsaturated aromatic rings is introduced in long chain fatty acids, it can hinder the beta-oxidation of aliphatic acid, improve heart uptake, extend cardiac muscle to be detained, to provide a kind of long-chain fatty acid derivative may be applied to clinical novel three carbonyls Tc 99m label.And the mark rate of the long-chain fatty acid derivative of Tc 99m label is high, and provide the feasibility and operability of clinical application.
Description
Technical field
The present invention relates to a kind of long chain fatty acid compounds in organic chemistry, medicinal chemistry art, more particularly to one
Novel three carbonyl of bipyridines of kind technetium-99 m labeled long-chain fatty acid derivative and its application.
Background technology
Angiocardiopathy, also known as circulation system disease, including it is coronary heart disease, cranial vascular disease, rheumatic heart disease, congenital
Heart disease etc..World Health Organization's report of global disease burden in 2004 points out, angiocardiopathy is global number one killer, 2004
Year, the whole world had 17,000,000 people to die of angiocardiopathy, and to before the year two thousand thirty, death toll is estimated more than 2,003,000,000[1].This disease
Circulatory system lesion originating from human body, but it is general all closely related with artery sclerosis, and artery sclerosis is due to arteries
Inner wall has fat, the depositions such as cholesterol, the formation of fibr tissue and calcification and the lesion that generates.This pathological development to heart is preced with
Coronary heart disease is then formed when shape artery.From natural arterial to asymptomatic atherosclerosis, arterial pulse pipe is narrow, needs for more than ten years
To the time of decades, but from asymptomatic artery sclerosis to Symptomatic artery sclerosis, such as coronary heart disease or apoplexy, it is only necessary to several
Minute.Therefore early diagnosis cardiovascular and cerebrovascular disease is the key that reduce the disease death rate.Radiopharmaceutical is in angiocardiopathy
Play an important roll in terms of early diagnosis.
PET/SPECT imaging techniques are considered as the current optimal path for realizing angiocardiopathy early diagnosis.It is so far
Only, existing developer includes：Myocardial perfusion imaging agent, myocardium agent, myocardial infarction developer, myocardial metabolic imaging
Agent, cardiac muscle nerve and receptor developer etc., myocardial metabolic agent have the metabolism and function status of studying cardiac muscular tissue
Significance.
By oxidation, the energy of generation forms main Energy supply materials of the ATP as cardiac muscle, root for aliphatic acid and glucose
Patient's myocardial ischaemia, heart failure etc., therefore aliphatic acid and glucose are may determine that according to its metabolic condition in cardiac muscle
Class myocardial metabolic agent can be used for studying metabolism and the function of cardiac muscle, they have important in the research of nuclear cardiology
Status.In cardiac muscle, beta oxidation of the acetyl coenzyme A from aliphatic acid of 50%-70%, therefore the oxidation of Myocardial Fatty Acids for
Cardiac asthenia is diagnosed, heart failure and myocardial ischaemia etc. are of great significance.99mThe myocardial metabolic agent of Tc labels can
It the case where for being positioned to myocardial ischemia, reacting myocardial metabolism changes of function, detect myocyte survival etc., is then examined for clinic
Disconnected angiocardiopathy provides reliable foundation.
Clinically leading metabolic imaging agent to be used at present has18F-FDG、11The PET developers of C- palmitates,123I-
IPPA and123The SPECT of I-BMIPP is imaged.But it there is no Tc-99m applied to clinical nucleic good properties and cheap
The metabolic imaging agent of label.
Currently, studies in China99mThe myocardial metabolic agent of Tc labels is fewer, and study in the world99mTc is marked
Myocardial metabolic agent realize higher heart uptake.The eighties has been applied to clinical diagnosis99mTc-MIBI cardiac muscles fill
Note imaging has certain accuracy to diagnosis of myocardial ischemia and necrosis, but it has one significantly not during Clinical practice
Foot place, due to99mTc-MIBI is mainly discharged through liver metabolism in vivo, when injection carries out myocardial imaging after 1-2 hours, liver
Interior radioactive delay usually influences myocardial imaging, therefore patient is needed to take fat meal after injection images half an hour in checking process
One promotes drug in liver to exclude, and reduces liver radioactivity, removes its influence to cardiac muscle, this is for a part of patient
Inconvenient.2004, Yasuhiro Magata etc.[10]The series fatty acid chemical combination of MAMA Tc-99m cores cooperation is synthesized
Object, results of animal show that the series fatty acid compound of Tc-99m labels has the higher initial intake of cardiac muscle and the quick heart
Muscle serum removes, within 2min [99mTc] the MAMA-HDA hearts/blood ratio be 3.6, by myocardial metabolism analysis be beta oxidation be metabolized, therefore
[99mTc] MAMA-HAD is a potential long chain fatty acids myocardial metabolic agent.
2006, Beijing Normal University Wang Xue was refined et al.[11]Using short chain diacid and MAMA ligands as starting material, synthesis
A series of Tc-99m cores label long-chain fatty acid derivative [99mTc]-MAMA-(CH2)nCOOH (n=14,15,16,
17).The Biodistribution data of normal mouse shows, when 5min intake percentage of this kind of marker in cardiac muscle be followed successively by
5.73.5.52.4.82.4.03 but principal bottom is higher and serum is except relatively slowly, the heart/blood value is low.
2007, Yasushi Arano[12]Deng report for the first time use [99mTc] CpTT-PA progress myocardial fatty acid metabolics
Measurement, the results showed that：ID/g is up to painstaking effort ratio in 3.85%, 10min and reaches 4.60 in 1min, myocardial metabolism experiment display
67% enter heart [99mTc] CpTT-PA absorbed, [99mTc] CpTT-propionic acid are after 6 beta-oxidation
Final product.2008, Yearn Seong Choe[13]Deng [99mTc] CpTT-PA architecture basics on remain with penta
The connected carbonyl of diene ring, synthesized compound [99mTc]CpTT-16-oxo-HAD.Results of animal is shown：ID/ in 1min
G is up to 9.03%, higher than the former, but its liver background increases very much, influences myocardial imaging, and the metabolisable form of the two is identical.
From data in literature as can be seen that99mThe advantages of aliphatic acid myocardial metabolic agent of Tc labels is that have higher cardiac muscle
Initial intake and quick myocardial metabolism, but it the shortcomings that be that metabolism in liver is slower, formed higher liver background influence it is aobvious
As effect, therefore there is prodigious research space in terms of the myocardial metabolic agent of Technetium labels.
Invention content
The object of the present invention is to provide a kind of long-chain fatty acid derivatives that three carbonyl of novel bipyridines is technetium-99 m labeled
And its application, the invention aim to solve the problem that at present99mThe derivative of fatty acid of Tc labels is applied to liver background when myocardial metabolic agent
High disadvantage reduces the fat-soluble of compound, to reduce liver background, in long chain fatty acids by rationally improving molecular structure
The unsaturated aromatic rings of middle introducing, can hinder the beta oxidation of aliphatic acid, improve heart uptake, extend cardiac muscle and be detained, to provide
It is a kind of to may be applied to the technetium-99 m labeled long-chain fatty acid derivative of clinical novel three carbonyl.The purpose of the present invention is logical
Following technical scheme is crossed to realize：
A kind of long-chain fatty acid derivative that three carbonyl of novel bipyridines is technetium-99 m labeled, three carbonyl of the bipyridines
The general formula of technetium-99 m labeled long-chain fatty acid derivative is
Wherein A is-CH2OrE is-CH2Or
na、nbIt is positive integer, naFor 1-16, nbIt is 0 or 1,
Further, nbWhen being 0, A is-CH2, E is-CH2OrnaFor the positive integer of 4-12, i.e., the described bipyridines
The structure of the technetium-99 m labeled long-chain fatty acid derivative of three carbonyls is chemical compounds I or II, and chemical compounds I and II is shown below：
(naFor the positive integer of 4-12)；
Preferably, the structure of the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of the bipyridines is：
Further, nbWhen being 0, A is-CH2, E isnaFor the positive integer of 4-12；Preferably, the bipyridines three
The structure of the technetium-99 m labeled long-chain fatty acid derivative of carbonyl isWherein n is 8-16.
Further, nbWhen being 1, R S, O or N, A are-CH2OrE is-CH2OrnaFor the just whole of 1-16
Number.
Further, nbWhen being 1, R S, O or N, A are-CH2OrE is-CH2OrnaFor the just whole of 1 or 8-14
Number.
Further, NaAnd nbWhen being 1, R is O or N, and A is-CH2OrE is-CH2OrPreferably, described
The structure of the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of bipyridines is：
Further, nbWhen being 1, R S, O or N, A are-CH2OrE is-CH2OrnaFor the just whole of 8-14
Number.
Further, the structure of the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of the bipyridines is：Wherein A is-CH2OrE is-CH2OrnaFor 8-14.
Further, nbIt is 1, naFor the positive integer of 8-14, R S, O or N, A isWhen, E is-CH2OrnbFor
1, naFor the positive integer of 8-14, R S, O or N, A is-CH2When, E is-CH2。
Further, the structure of the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of the bipyridines is：
A kind of application of the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of novel bipyridines, double pyrroles
The technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of pyridine class is applied as myocardial developer.
The present invention provides a kind of long-chain fatty acid derivative that three carbonyl of novel bipyridines is technetium-99 m labeled and its answer
With mainly having the advantage that：Liver background is effectively reduced, fac- [3 (H2O) 3 of 99mTc (CO)]+intermediate mark is passed through
Note, improves mark rate, provides the feasibility and operability of clinical application.
Description of the drawings
Below according to attached drawing, invention is further described in detail.
Fig. 1 is the compound III described in the embodiment of the present invention 51HNMR；
Fig. 2 is the compounds Ⅳ described in the embodiment of the present invention 51HNMR；
Fig. 3 is the compounds Ⅳ described in the embodiment of the present invention 513CNMR；
Fig. 4 is the MS of the compounds Ⅳ described in the embodiment of the present invention 5；
Fig. 5 is V a of compound described in the embodiment of the present invention 51HNMR；
Fig. 6 is V a of compound described in the embodiment of the present invention 513CNMR；
Fig. 7 is the MS of V a of compound described in the embodiment of the present invention 5；
Fig. 8 be described in the embodiment of the present invention 3 intermediate [99mTc(CO)3(H2O)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 61HNMR；
Figure 11 is the compounds Ⅳ described in the embodiment of the present invention 61HNMR；
Figure 12 is the compounds Ⅳ described in the embodiment of the present invention 613CNMR；
Figure 13 is the compound V described in the embodiment of the present invention 81HNMR；
Figure 14 is the compound V described in the embodiment of the present invention 813CNMR；
Figure 15 is the MS of the compound V described in the embodiment of the present invention 8；
Figure 16 is VI a of compound described in the embodiment of the present invention 81HNMR。
Specific implementation mode
As illustrated in figs. 1-16, a kind of long-chain that three carbonyl of novel bipyridines is technetium-99 m labeled described in the embodiment of the present invention
Derivative of fatty acid and its application.Illustrate specific implementation mode by taking specific experiment case as an example below, it should be understood that this place
The specific embodiment of description is only used to explain the present invention, is not intended to limit the present invention.
Embodiment 1
The general structure of the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of novel bipyridines is：
Wherein A is-CH2OrE is-CH2Orna、nbIt is positive integer, naFor 1-16, nbIt is 0 or 1, and works as nb
When being 1, R S, O or N.
As further preferred embodiment, nbIt is-CH for 0, A2, E is-CH2OrWhen, three carbonyl of the bipyridines
The structure of the technetium-99 m labeled long-chain fatty acid derivative of base is：
Wherein, naFor the positive integer of 4-12；
As further preferred embodiment, the technetium-99 m labeled long chain fatty acids of three carbonyl of the bipyridines derive
The structure of object is：Wherein, naFor the positive integer of 4-12；
As further preferred embodiment, nbWhen being 1, R S, O or N, A are-CH2OrE is-CH2Or
naFor the positive integer of 1-16.
As further preferred embodiment, nbWhen being 1, R S, O or N, A are-CH2OrE is-CH2Or
naFor the positive integer of 1 or 8-14.
As further preferred embodiment, NaAnd nbWhen being 1, R is O or N, and A is-CH2OrE is-CH2OrIt is further preferred that the structure of the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of the bipyridines is：
As further preferred embodiment, nbWhen being 1, R S, O or N, A are-CH2OrE is-CH2OrnaFor the positive integer of 8-14.
As further preferred embodiment, the technetium-99 m labeled long chain fatty acids of three carbonyl of the bipyridines derive
The structure of object is：Wherein A is-CH2OrE is-CH2OrnaFor 8-
14。
As further preferred embodiment, nbIt is 1, naFor the positive integer of 8-14, R S, O or N, A isWhen, E
For-CH2OrnbIt is 1, naFor the positive integer of 8-14, R S, O or N, A is-CH2When, E is-CH2.It is highly preferred that described double
The structure of the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of pyridines is： Wherein, n2 is 8~14.
Embodiment 2：The synthetic route of following compounds is：
1、Wherein n1For 8-16, R S, O or N；
2、Wherein n2For 8-14, R S, O or N；
3、Wherein n2For 8-14, R S, O or N；
4、Wherein n2For 8-14, R S, O or N；
Embodiment 3~13 is to choose in embodiment 2 per a compound in class compound as representing, according to embodiment
Its specific synthesis step is described in detail in synthetic route in 2, and the synthesis step of other similar compounds is consistent with process in detail below,
Here it is not repeating to write exactly one by one.
Embodiment 3：The preparation of marker intermediate
fac-[99mTc(CO)3(H2O)3]+The preparation of intermediate：Take 5mg Na2CO3,10mg NaBH4,15mg tartaric acid
Potassium sodium is added 1ml physiological saline, fully shakes up thereto in 10mL penicillin bottles, is taken out with the disposable needle tubing of 10ml true
Sky leads to gas 15min in carbon monoxide, empties air in bottle, is then injected into 2ml Na99mTcO4Eluent (about 13mci), 80
DEG C oil bath continuous heating 30min (reaction process one leads directly to CO gas), it is cooling, obtain intermediate [99mTc(CO)3
(H2O)3]+, for use, the Intermediates Intermediate [99mTc(CO)3(H2O)3]+HPLC figures it is as shown in Figure 8.
Synthesize the intermediate [NEt of the complex of rhenium4]2[Re(CO)3Br3] preparation：Under nitrogen protection, it weighs
505.4mg (1.2mmol) bromination tetraethyl amine closes rhenium with 415.2mg (1.0mmol) bromination pentacarbonyl, and diethylene glycol diformazan is added
Ether solvents 100ml is first slowly warmed up 80 DEG C under magnetic agitation, and stirring waits for that solid is completely dissolved in a moment, then is warming up to 120 DEG C
Reaction overnight, there is faint yellow solid generation in solution, filter solid is crossed while hot, then with cold diethylene glycol dimethyl ether and anhydrous second
Ether washs for several times, is placed in drying in vacuum desiccator, and the solid powder after drying is washed with a small amount of absolute ethyl alcohol again, is filtered, very
Empty dry product [NEt4]2[Re(CO)3Br3].Obtain light yellow solid product 680mg, yield 86.7%, fusing point 302.9-
305.4, not repurity is directly used in and reacts in next step.
It should be noted that：All radioactive compounds are determined according to the complex of its non-radioactive analogs rhenium
Its structure.Since the element technetium marked in compound does not have corresponding stable technetium compound to determine the structure of radioactive technetium
And therefore appearance time has selected element rhenium (Re) labeled compound similar with element technetium property to determine mtc labeled
The structure of compound.
Embodiment 4：Preparation
1. by the SOCl of 30ml under condition of ice bath2It is added dropwise in the dodecanedioic acid of 4.60g, it is small to continue stirring half
When, it is refluxed overnight under the conditions of 90 DEG C of oil bath, removes extra SOCl2, transparent oil product, as compound ii are obtained, no
It is further purified, gives over to and use in next step.
2. the absolute methanol of 5ml is added into the step 1. compound ii of middle gained, 2h is stirred at 60 DEG C, is mainly produced
The mixture that object is III, does not deal with, and gives over to and uses in next step.
3. bis- (2- pyridylmethyls) amine of 4.0g are dissolved in dry dichloromethane solution, under ice bath, and it is added dropwise dropwise
Into the step 2. compound III of gained, half an hour is stirred, the dichloromethane dissolved with 2.8g aluminum trichloride (anhydrous)s, room temperature are added
5h is stirred, is then handled with the hydrochloric acid of 1mol/L, dichloromethane extracts five times, anhydrous magnesium sulfate drying, with petroleum ether/second
Acetoacetic ester=8/3 (centesimal triethylamine solution is added) carries out silica gel column chromatography, obtains compounds Ⅳ, the synthesis production of three steps
Rate is 34.6%.
4. by the [NEt of 140mg (0.17mmol)4]2[Re(CO)3Br3] be dissolved in 10ml absolute methanols, compounds Ⅳ
72.25mg (0.17mmol) is dissolved in 6ml absolute methanols, and is slowly added drop-wise in above-mentioned solution, and 4h is stirred at room temperature, and (TLC is supervised
Survey) reaction finishes, and rotary evaporation removes solvent, adds potassium hydroxide solution 2ml, the 6ml absolute methanol of the 1M now matched, 80 DEG C
1h hydrolysis is reacted, reaction finishes, and is neutralized with the hydrochloric acid solution of 2M, until solution is spin-dried in acidity, is dissolved with a small amount of methanol, mistake
Insoluble matter is filtered, dichloromethane is used:Methanol=15:1 (1% triethylamine and 0.5% glacial acetic acid is added) is that solvent is divided
From final product, as rhenium label V a of compound, yield 45.6%.
5. compounds Ⅳ is made into the aqueous solution of 1mg/ml, thereto be added 1ml (about 2-3mci) prepare [99mTc
(CO)3(H2O)3]+Intermediate is placed in 80 DEG C of oil bath with hydrochloric acid tune PH ≈ 8 and reacts 30min, then added 1ml 0.8M
NaOH solution react 30min, reflection finishes, and with the HCl tune PH of 1M to acidity, vacuum distillation is dissolved in proper amount of methanol, filtering,
Concentration, obtains target product V, yield 68.2%.
Embodiment 5：Preparation
1. 13.97g (0.05mol) 12- bromo-dodecane acid is dissolved in the dichloromethane of 200ml dryings, 6 drop DMF are added and urge
Change adds 6ml oxalyl chlorides, is stirred at room temperature 4 hours, rotary evaporation, removes dichloromethane and excessive oxalyl chloride, obtains chemical combination
Object II, does not deal with, and is directly used in and reacts in next step.
2. the dichloromethane that 70ml is dried is added into the 1. compound ii of middle gained, under the conditions of ice-water bath, it is slowly added dropwise
7.44g (0.05mol) is dissolved in the thiophene methyl propionate in 40ml dichloromethane solutions, is added dropwise after 1h, and stirring is about
6.68g aluminum trichloride (anhydrous)s are added portionwise in 30min under the conditions of ice-water bath, heat up, are stirred overnight naturally.TLC is monitored, reaction
After the completion, it under ice bath, is extracted with the hydrochloric acid of 1mol/L, then with dichloromethane (3*50ml), merges lower layer's organic solution, used
Solvent, the used silica gel column purification (petroleum ether of crude product are removed in appropriate anhydrous magnesium sulfate drying, filtering, decompression rotation:Ethyl acetate=
10:1~8:1) 14.0g yellow solid matters, as compound III, three step comprehensive yieds 67.3%, are obtained；Compound III1HNMR figures are as shown in Figure 1.
3. by bis- (2- pyridylmethyls) amine of 843.75mg (4.2mmol), DIEA 1.5ml (8.4mmol) and KI 69mg
(0.42mmol) is dissolved in 40ml acetonitriles, under addition 1.5g (3.6mmol) compound III thereto, nitrogen protection, is taken the photograph 70
It is stirred 2 hours under family name's degree, so that it is sufficiently mixed, then be warming up to 85 degrees Celsius, be refluxed overnight, TLC monitorings, reaction finishes rotation and went
Acetonitrile is measured, saturated sodium carbonate solution, water, saturated common salt washing is used respectively, is extracted with dichloromethane, merge organic layer, anhydrous sulphur
Sour magnesium drying, filtering spin off dichloromethane, and crude product crosses silica gel column purification, (petroleum ether of 1% triethylamine is added:Ethyl acetate
=8:3 solution are solvent), 1.3g yellow oily pure compounds, as compounds Ⅳ, yield 67.4%.Compounds Ⅳ1HNMR、13CNMR, MS spectrogram difference are as shown in Figure 2,3, 4.
4. 4. reaction process, obtains V a of target product with the step in embodiment 4, yield 54.3%, V a's of target product1HNMR、13CNMR, MS spectrogram are respectively as shown in Fig. 5,6,7.
5. 5. reaction process, obtains target product V, yield 70.5%, the target product V with the step in embodiment 4
Redio-HPLC spectrograms it is as shown in Figure 9.
It can determine the structure of the target product V by the above collection of illustrative plates.
Embodiment 6：Preparation
1. 13.37g (0.05mol) 11- bromo-n-11 acid is dissolved in the dichloromethane of 200ml dryings, 6 drop DMF are added and urge
Change adds 6ml oxalyl chlorides, is stirred at room temperature 4 hours, rotary evaporation, removes dichloromethane and excessive oxalyl chloride, obtains chemical combination
Object II, does not deal with, and is directly used in and reacts in next step.
2. the dichloromethane that 70ml is dried is added into step 1. middle gained compound ii, under the conditions of ice-water bath, slow drop
Add 8.40g (0.05mol) to be dissolved in the furanpropionic acid ethyl ester in 40ml dichloromethane solutions, be added dropwise after 1h, stirring is about
6.68g aluminum trichloride (anhydrous)s are added portionwise in 30min under the conditions of ice-water bath, heat up, are stirred overnight naturally.TLC is monitored, reaction
After the completion, it under ice bath, is extracted with the hydrochloric acid of 1mol/L, then with dichloromethane (3*50ml), merges lower layer's organic solution, used
Solvent, the used silica gel column purification (petroleum ether of crude product are removed in appropriate anhydrous magnesium sulfate drying, filtering, decompression rotation:Ethyl acetate=
10:1~8:1) 14.0g yellow solid matters, as compound III, are obtained, two step comprehensive yieds 67.3%, the compound III
1HNMR spectrograms are as shown in Figure 10；
3. by bis- (2- pyridylmethyls) amine of 843.75mg (4.2mmol), DIEA 1.5ml (8.4mmol) and KI 69mg
(0.42mmol) is dissolved in 40ml acetonitriles, under addition 1.5g (3.6mmol) compound III thereto, nitrogen protection, is taken the photograph 70
It is stirred 2 hours under family name's degree, so that it is sufficiently mixed, then be warming up to 85 degrees Celsius, be refluxed overnight, TLC monitorings, reaction finishes rotation and went
Acetonitrile is measured, is washed respectively with saturated sodium carbonate solution (2*30ml), water (2*30ml), saturated salt solution (2*30ml), uses dichloromethane
Alkane (3*30ml) extracts, and merges organic layer, anhydrous magnesium sulfate drying, and filtering spins off dichloromethane, it is pure that crude product crosses silicagel column
Change, (petroleum ether of 1% triethylamine is added:Ethyl acetate=8:3 solution be solvent), 1.25g yellow oily pure compounds,
As compounds Ⅳ, yield 63.5%, the compounds Ⅳ1HNMR、13CNMR spectrograms are as shown in figure 11.
4. 4. reaction process, obtains V a of target product, yield 48.6% with the step in embodiment 4.
5. 5. reaction process, obtains target product V, yield 78.3% with the step in embodiment 4.
Embodiment 7：Preparation
1. 13.97g (0.05mol) 12- bromo-dodecane acid is dissolved in the dichloromethane of 200ml dryings, 6 drop DMF are added
Catalysis adds 6ml oxalyl chlorides, is stirred at room temperature 4 hours, rotary evaporation, removes dichloromethane and excessive oxalyl chloride, as changes
Object II is closed, is not dealt with, is directly used in and reacts in next step.
2. the dichloromethane that 70ml is dried is added into 1. middle gained compound ii, under the conditions of ice-water bath, it is slowly added dropwise
8.40g (0.05mol) is dissolved in the pyrrole propanoic acid methyl esters in 40ml dichloromethane solutions, is added dropwise after 1h, and stirring is about
6.68g aluminum trichloride (anhydrous)s are added portionwise in 30min under the conditions of ice-water bath, heat up, are stirred overnight naturally.TLC is monitored, reaction
After the completion, it under ice bath, is extracted with the hydrochloric acid of 1mol/L, then with dichloromethane (3*50ml), merges lower layer's organic solution, used
Solvent, the used silica gel column purification (petroleum ether of crude product are removed in appropriate anhydrous magnesium sulfate drying, filtering, decompression rotation：Ethyl acetate=
10:1~8:1) 14.0g yellow solid matters, two step comprehensive yieds 67.3%, are obtained；
3. by bis- (2- pyridylmethyls) amine of 843.75mg (4.2mmol), DIEA 1.5ml (8.4mmol) and KI 69mg
(0.42mmol) is dissolved in 40ml acetonitriles, under addition 1.5g (3.6mmol) compound III thereto, nitrogen protection, is taken the photograph 70
It is stirred 2 hours under family name's degree, so that it is sufficiently mixed, then be warming up to 85 degrees Celsius, be refluxed overnight, TLC monitorings, reaction finishes rotation and went
Acetonitrile is measured, is washed respectively with saturated sodium carbonate solution (2*30), water (2*30), saturated salt solution (2*30), with dichloromethane (3*
30) it extracts, merges organic layer, anhydrous magnesium sulfate drying, filtering spins off dichloromethane, and crude product crosses silica gel column purification, (is added
The petroleum ether of 1% triethylamine:Ethyl acetate=8:3 solution be solvent), 0.7g yellow oily pure compounds, yield
36.5%；
4. 4. reaction process, obtains V a of target product, yield 46.8% with the step in embodiment 4.
5. 5. reaction process, obtains target product V, yield 75.6% with the step in embodiment 4.
Embodiment 8：Preparation
1. 13.97g (0.05mol) 12- bromo-dodecane acid is dissolved in the dichloromethane of 200ml dryings, 6 drop DMF are added and urge
Change adds 6ml oxalyl chlorides, is stirred at room temperature 4 hours, rotary evaporation, removes dichloromethane and excessive oxalyl chloride to get chemical combination
Object II, does not deal with, and is directly used in and reacts in next step.
2. to the step dichloromethane that 1. middle gained acyl chlorides addition 70ml is dried, under the conditions of ice-water bath, 7.44g is slowly added dropwise
(0.05mol) is dissolved in the thiophene methyl propionate in 40ml dichloromethane solutions, is added dropwise after 1h, about 30min is stirred, in ice
6.68g aluminum trichloride (anhydrous)s are added portionwise under water bath condition, heats up, is stirred overnight naturally.TLC is monitored, after the completion of reaction, ice bath
Under, it is extracted with the hydrochloric acid of 1mol/L, then with dichloromethane (3*50ml), merges lower layer's organic solution, with appropriate anhydrous sulphur
Solvent, the used silica gel column purification (petroleum ether of crude product are removed in sour magnesium drying, filtering, decompression rotation：Ethyl acetate=10：1-8：1) it, obtains
14.0g yellow solid matters, as compound III, two step comprehensive yieds 67.3%；
3. by bis- (2- pyridylmethyls) amine of 843.75mg (4.2mmol), DIEA 1.5ml (8.4mmol), KI69mg
(0.42mmol) is dissolved in 40ml acetonitriles, under addition 1.5g (3.6mmol) compound III thereto, nitrogen protection, is taken the photograph 70
It is stirred 2 hours under family name's degree, so that it is sufficiently mixed, then be warming up to 85 degrees Celsius, be refluxed overnight, TLC monitorings, reaction finishes rotation and went
Acetonitrile is measured, is washed respectively with saturated sodium carbonate solution (2*30), water (2*30), saturated salt solution (2*30), with dichloromethane (3*
30) it extracts, merges organic layer, anhydrous magnesium sulfate drying, filtering spins off dichloromethane, and crude product crosses silica gel column purification, (is added
The petroleum ether of 1% triethylamine：Ethyl acetate=8：3 solution are solvent), 1.3g yellow oily pure compounds, as chemical combination
Object IV, yield 67.4%.
4. 1.54g (2.8mmol) compounds Ⅳ is dissolved in the mixed liquor of 15ml trifluoroacetic acids and 15ml dichloromethane, it will
745g sodium borohydrides are added portionwise, and 5h is stirred at room temperature, and TLC monitors (product point is more little higher than raw material point), and reaction finishes, with two
Chloromethanes dilutes, and with the sodium hydroxide solution tune ph=10 of 1M, is extracted with dichloromethane, crude product petroleum ether：Ethyl acetate
(triethylamine for adding 1%)=3:1 crosses silicagel column for solvent, obtains 0.56g pure compounds V (pale yellowish oil compound), yield
37.3%, the compound V1HNMR、13CNMR, MS figure are respectively as shown in Figure 13~15.
5. 4. reaction process, obtains VI a of target product, yield 43.9%, VI a of the target product with the step in embodiment 4
's1HNMR is as shown in figure 16.
6. 5. reaction process, obtains target product VI, yield 78.3% with the step in embodiment 4.
Embodiment 9：Preparation
1. 13.97g (0.05mol) 12- bromo-dodecane acid is dissolved in the dichloromethane of 200ml dryings, 6 drop DMF are added and urge
Change adds 6ml oxalyl chlorides, is stirred at room temperature 4 hours, rotary evaporation, removes dichloromethane and excessive oxalyl chloride to get chemical combination
Object II, does not deal with, and is directly used in and reacts in next step.
2. to the step dichloromethane that 1. middle gained acyl chlorides addition 70ml is dried, under the conditions of ice-water bath, 8.40g is slowly added dropwise
(0.05mol) is dissolved in the furanpropionic acid ethyl ester in 40ml dichloromethane solutions, is added dropwise after 1h, about 30min is stirred, in ice
6.68g aluminum trichloride (anhydrous)s are added portionwise under water bath condition, heats up, is stirred overnight naturally.TLC is monitored, after the completion of reaction, ice bath
Under, it is extracted with the hydrochloric acid of 1mol/L, then with dichloromethane (3*50ml), merges lower layer's organic solution, with appropriate anhydrous sulphur
Solvent, the used silica gel column purification (petroleum ether of crude product are removed in sour magnesium drying, filtering, decompression rotation:Ethyl acetate=10:1~8:1),
Obtain 14.0g yellow solid matters, as compound III, two step comprehensive yieds 67.3%
3. by bis- (2- pyridylmethyls) amine of 843.75mg (4.2mmol), DIEA 1.5ml (8.4mmol), KI 69mg
(0.42mmol) is dissolved in 40ml acetonitriles, under addition 1.5g (3.6mmol) compound III thereto, nitrogen protection, at 70 DEG C
Lower stirring 2 hours, makes it be sufficiently mixed, then be warming up to 85 degrees Celsius, is refluxed overnight, and TLC monitorings, reaction finishes vacuum distillation and removes
Excess acetonitrile is removed, is washed respectively with saturated sodium carbonate solution (2*30), water (2*30), saturated salt solution (2*30), uses dichloromethane
(3*30) is extracted, and merges organic layer, anhydrous magnesium sulfate drying, and filtering spins off dichloromethane, crude product is crossed silica gel column purification, (added
Enter the petroleum ether of 1% triethylamine:Ethyl acetate=8:3 solution are solvent), 1.25g yellow oily pure compounds are obtained, are as changed
Close object IV, yield 63.5%.
4. 1.52g (2.8mmol) compounds Ⅳ is dissolved in the mixed liquor of 15ml trifluoroacetic acids and 15ml dichloromethane, it will
745g sodium borohydrides are added portionwise, and 5h are stirred at room temperature, TLC monitorings, reaction is finished, diluted with dichloromethane, with the hydroxide of 1M
Sodium solution tune ph=10, is extracted with dichloromethane, crude product petroleum ether:Ethyl acetate (triethylamine for adding 1%)=3:1 is exhibition
It opens agent and crosses silicagel column, obtain 0.58g pure compounds (pale yellowish oil compound), as compound V, yield 37.9%.
5. 4. reaction process, obtains VI a of target product, yield 49.8% with the step in embodiment 4.
6. 5. reaction process, obtains target product VI, yield 76.3% with the step in embodiment 4.
Embodiment 10：Preparation
1. 13.97g (0.05mol) 12- bromo-dodecane acid is dissolved in the dichloromethane of 200ml dryings, 6 drop DMF are added and urge
Change adds 6ml oxalyl chlorides, is stirred at room temperature 4 hours, rotary evaporation, removes dichloromethane and excessive oxalyl chloride to get chemical combination
Object II, does not deal with, and is directly used in and reacts in next step.
2. the dichloromethane that 70ml is dried is added into step 1. middle gained compound ii, under the conditions of ice-water bath, slow drop
Add 8.40g (0.05mol) to be dissolved in the pyrrole propanoic acid methyl esters in 40ml dichloromethane solutions, be added dropwise after 1h, stirring is about
6.68g aluminum trichloride (anhydrous)s are added portionwise in 30min under the conditions of ice-water bath, heat up, are stirred overnight naturally.TLC is monitored, reaction
After the completion, it under ice bath, is extracted with the hydrochloric acid of 1mol/L, then with dichloromethane (3*50ml), merges lower layer's organic solution, used
Solvent, the used silica gel column purification (petroleum ether of crude product are removed in appropriate anhydrous magnesium sulfate drying, filtering, decompression rotation:Ethyl acetate=
10:1-8:1) 14.0g yellow solid matters, as compound III, two step comprehensive yieds 67.3%, are obtained
3. by bis- (2- pyridylmethyls) amine of 843.75mg (4.2mmol), DIEA 1.5ml (8.4mmol) and KI 69mg
(0.42mmol) is dissolved in 40ml acetonitriles, under addition 1.5g (3.6mmol) compound III thereto, nitrogen protection, is taken the photograph 70
It is stirred 2 hours under family name's degree, so that it is sufficiently mixed, then be warming up to 85 degrees Celsius, be refluxed overnight, TLC monitorings, reaction finishes rotation and went
Acetonitrile is measured, is washed respectively with saturated sodium carbonate solution (2*30), water (2*30), saturated salt solution (2*30), with dichloromethane (3*
30) it extracts, merges organic layer, anhydrous magnesium sulfate drying, filtering spins off dichloromethane, and crude product crosses silica gel column purification, (is added
The petroleum ether of 1% triethylamine:Ethyl acetate=8:3 solution are solvent), 0.7g yellow oily pure compounds, as chemical combination
Object IV, yield 36.5%.
4. 1.49g (2.8mmol) compounds Ⅳ is dissolved in the mixed liquor of 15ml trifluoroacetic acids and 15ml dichloromethane, it will
745g sodium borohydrides are added portionwise, and 5h are stirred at room temperature, TLC monitorings, reaction is finished, diluted with dichloromethane, with the hydroxide of 1M
Sodium solution tune ph=10, is extracted with dichloromethane, crude product petroleum ether:Ethyl acetate (triethylamine for adding 1%)=3:1 is exhibition
It opens agent and crosses silicagel column, obtain 0.73g pure compounds (pale yellowish oil compound), as compound V, yield 50.3%.
5. 4. reaction process, obtains VI a of target product, yield 47.9% with the step in embodiment 4.
6. 5. reaction process, obtains target product VI, yield 74.6% with the step in the 1 of the present embodiment.
Embodiment 11：Preparation
1. by the SO of 30ml under condition of ice bath2Cl is added dropwise in the dodecanedioic acid (i.e. chemical compounds I) of 4.60g,
Continue to stir half an hour, return stirring is stayed overnight under the conditions of 90 DEG C of oil bath, removes extra SO2Cl obtains transparent oil product,
That is compound ii is not further processed, and is given over to and is used in next step；
2. bis- (2- pyridylmethyls) amine of 4.0g are dissolved in dry dichloromethane solution, under ice bath, and it is added dropwise dropwise
Into the step 1. compound ii of gained, half an hour is stirred, the dichloromethane dissolved with 2.8g aluminum trichloride (anhydrous)s, room temperature are added
5h is stirred, compound III is obtained, it is without any processing, it is used directly for reacting in next step；
3. 3.40g 3- (2- thienyls)-methyl propionate is dissolved in the dichloromethane solution of 20ml, under condition of ice bath, by
In the compound III obtained in being added dropwise to step 2., after half an hour, then it is slowly added into the aluminum trichloride (anhydrous) of 2.80g, room temperature
Under the conditions of stir 5h, under condition of ice bath, the hydrochloric acid solution of 1mol/l is slowly added into above-mentioned mixed solution, until solution is in acid
Property, it is used in combination dichloromethane to extract five times, anhydrous magnesium sulfate drying (is added centesimal with petrol ether/ethyl acetate=8/3
Triethylamine solution) silicagel column is crossed, compounds Ⅳ is obtained, three step comprehensive yieds are 32.6%.
4. reaction process with the step in embodiment 4 4., as rhenium label V a of compound, yield 51.2%.
5. 5. reaction process, obtains target product V, yield 68.4% with the step in embodiment 4.
Embodiment 12：Preparation
1. by the SO of 30ml under condition of ice bath2Cl is added dropwise in the dodecanedioic acid (i.e. chemical compounds I) of 4.60g,
Continue to stir half an hour, return stirring is stayed overnight under the conditions of 90 DEG C of oil bath, removes extra SO2Cl obtains transparent oil product,
That is compound ii is not further processed, and is given over to and is used in next step；
2. bis- (2- pyridylmethyls) amine of 4.0g are dissolved in dry dichloromethane solution, under ice bath, and it is added dropwise dropwise
Into the step 1. compound ii of gained, half an hour is stirred, the dichloromethane dissolved with 2.8g aluminum trichloride (anhydrous)s, room temperature are added
5h is stirred, compound III is obtained, it is without any processing, it is used directly for reacting in next step.
3. 3.36g 3- (2- furyls)-ethyl propionate is dissolved in the dichloromethane solution of 20ml, under condition of ice bath, by
In the compound III obtained in being added dropwise to step 2., after half an hour, then it is slowly added into the aluminum trichloride (anhydrous) of 2.80g, room
It stirs 5h under the conditions of temperature, under condition of ice bath, the hydrochloric acid solution of 1mol/l is slowly added into above-mentioned mixed solution, until solution is in
Acidity is used in combination dichloromethane to extract five times, and anhydrous magnesium sulfate drying (is added 1 percent with petrol ether/ethyl acetate=8/3
Triethylamine solution) cross silicagel column, obtain compounds Ⅳ, three step comprehensive yieds are 40.2%.
4. reaction process with the step in embodiment 4 4., as rhenium label V a of compound, yield 50.9%.
5. 5. reaction process, obtains target product V, yield 65.8% with the step in embodiment 4.
Embodiment 13：Preparation
1. by the SO of 30ml under condition of ice bath2Cl is added dropwise in the dodecanedioic acid (i.e. chemical compounds I) of 4.60g,
Continue to stir half an hour, return stirring is stayed overnight under the conditions of 90 DEG C of oil bath, removes extra SO2Cl obtains transparent oil product,
That is compound ii is not further processed, and is given over to and is used in next step；
2. bis- (2- pyridylmethyls) amine of 4.0g are dissolved in dry dichloromethane solution, under ice bath, and it is added dropwise dropwise
Into the step 1. compound ii of gained, half an hour is stirred, the dichloromethane dissolved with 2.8g aluminum trichloride (anhydrous)s, room temperature are added
5h is stirred, product III is obtained, it is without any processing, it is used directly for reacting in next step；
3. 3.06g 3- (2- pyrrole radicals)-methyl propionate is dissolved in the dichloromethane solution of 20ml, under condition of ice bath, by
In the compound III obtained in being added dropwise to step 2., after half an hour, then it is slowly added into the aluminum trichloride (anhydrous) of 2.80g, room
It stirs 5h under the conditions of temperature, under condition of ice bath, the hydrochloric acid solution of 1mol/l is slowly added into above-mentioned mixed solution, until solution is in
Acidity is used in combination dichloromethane to extract five times, and anhydrous magnesium sulfate drying (is added 1 percent with petrol ether/ethyl acetate=8/3
Triethylamine solution) cross silicagel column, obtain compounds Ⅳ, three step comprehensive yieds are 33.2%.
4. 4. reaction process, obtains V a of target product, yield 48.5% with the step in embodiment 4.
5. 5. reaction process, obtains target product V, yield 63.9% with the step in embodiment 4.
Embodiment:14
5 gained compound V of embodiment is injected for mouse, then bio distribution result of the compound in Mice Body is as follows
(%ID/g, n=5) shown in table.Compound V is
As seen from the above table, the bio distribution feature of the compound V is that heart uptake is reachable after injecting drug 1min
Quick elution is presented when 4.24 ± 0.93%ID/g, 1-5min, has reached 2.20 ± 0.35%ID/g in 5min；After 5min
Elution speed is slack-off, and the 1.14%ID/g of 30min is fallen below by the 2.205%ID/g of 5min；30-120min elution speeds are more
Slowly, elution speed is slower on the whole, and anelasticity is preferable, illustrates to be introduced into thiphene ring in technetium-99 m labeled long chain fatty acids,
Play the role of extending the residence time.In addition, the compound effectively reduces liver background, when 1min liver intake for 7.79 ±
0.76%ID/g, liver absorb highest and 5min after injection occur, are 15.75 ± 2.28%ID/g, than the myocardium generation reported at present
The liver background for thanking to developer wants low, illustrates that the compound is likely to become a potential myocardial metabolic agent.
The present invention is not limited to above-mentioned preferred forms, anyone the related present invention done under the inspiration of the present invention
Any modification or change, it is every that there is same as the present application or similar technical solution, all fall within protection scope of the present invention
Within.
Claims (6)
1. a kind of long-chain fatty acid derivative that three carbonyl of novel bipyridines is technetium-99 m labeled, it is characterised in that：Double pyridines
The general formula of the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of class is
Wherein A is-CH2OrE is-CH2Or
na、nbIt is positive integer, nbWhen being 1, R S, O or N, naFor the positive integer of 1 or 8-14.
2. the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of novel bipyridines according to claim 1, special
Sign is：naAnd nbWhen being 1, R is O or N.
3. the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of novel bipyridines according to claim 2, special
Sign is：naFor the positive integer of 8-14.
4. the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of novel bipyridines according to claim 3, special
Sign is：A isWhen, E is-CH2OrA is-CH2When, E is-CH2。
5. the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of novel bipyridines according to claim 4, special
Sign is：The structure of the technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of the bipyridines is：
6. the technetium-99 m labeled long chain fatty acids of three carbonyl of novel bipyridines according to any one in right 1 to 5
Derivative is as the application prepared in myocardial developer, it is characterised in that：The technetium-99 m labeled long-chain of three carbonyl of bipyridines
Derivative of fatty acid is applied as myocardial developer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510571327.9A CN105198930B (en) | 2015-09-09 | 2015-09-09 | The technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of bipyridines and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510571327.9A CN105198930B (en) | 2015-09-09 | 2015-09-09 | The technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of bipyridines and its application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105198930A CN105198930A (en) | 2015-12-30 |
| CN105198930B true CN105198930B (en) | 2018-10-09 |
Family
ID=54946919
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510571327.9A Expired - Fee Related CN105198930B (en) | 2015-09-09 | 2015-09-09 | The technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of bipyridines and its application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105198930B (en) |
Citations (1)
| 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 |
-
2015
- 2015-09-09 CN CN201510571327.9A patent/CN105198930B/en not_active Expired - Fee Related
Patent Citations (1)
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis, characterization and biodistribution of new fatty acids conjugates bearing N,N,N-donors incorporated [99mTc/Re(CO)3]+;Huahui Zeng et al.;《Dalton Trans.》;20121210;第2894-2901页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105198930A (en) | 2015-12-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107245087B (en) | 99mTc marks glucosan derivative and preparation method and application containing isonitrile | |
| CN103113354B (en) | PEGylated benzyltriazolyl pyridazinone compounds, and preparation method and application thereof | |
| Ono et al. | Development of novel β-amyloid probes based on 3, 5-diphenyl-1, 2, 4-oxadiazole | |
| CN112175025B (en) | Glucose derivative containing benzene ring and application thereof | |
| CN111138504A (en) | A kind of99mTc-CNPEDG complex and preparation method and application thereof | |
| CN107522673B (en) | 1,2,4, 5-tetrazine compound for bioorthogonal reaction and preparation method and application thereof | |
| CN110183493B (en) | 99 mTechnetium labeled complex and application thereof in diagnosis of non-small cell lung cancer | |
| Mukai et al. | Design of Ga–DOTA-based bifunctional radiopharmaceuticals: Two functional moieties can be conjugated to radiogallium–DOTA without reducing the complex stability | |
| Choi et al. | Synthesis and evaluation of an 125I-labeled azide prosthetic group for efficient and bioorthogonal radiolabeling of cyclooctyne-group containing molecules using copper-free click reaction | |
| CN109320557A (en) | 99mTc(CO)3The Pa Boxini derivative and preparation method and application containing isonitrile of core label | |
| CN101891791B (en) | Derivate for labeling bile acid and reference compound, preparation method and application thereof | |
| CN105198930B (en) | The technetium-99 m labeled long-chain fatty acid derivative of three carbonyl of bipyridines and its application | |
| CN102311459B (en) | Novel technetium-99m-labeled higher fatty acid derivative | |
| CN101555263B (en) | D-glucose dithiocarbamate complex marked by <99m>TcO, preparation method and applications thereof | |
| CN114031652B (en) | Glucose derivative containing cyclohexane and application thereof | |
| CN113583066B (en) | Mannose derivative and application thereof | |
| CN113387927B (en) | Nitroimidazole derivative for preparing hypoxia imaging agent and preparation method and application thereof | |
| CN108586524B (en) | Fluoro phosphine oxide-type compound and its application in positron emission imaging | |
| CN103772440B (en) | Technetium-99m-labeled higher fatty acid derivative | |
| CN105524113B (en) | 99mTcN cores mark glucose dithiocarbamate complexes and preparation method and application containing triazole ring | |
| CN106631863B (en) | The radiation synthetic method of sub- glutamic acid-type PET developers | |
| CN105001274B (en) | Complex, the Preparation method and use of a kind of Glucosamine derived ligand compound and preparation method, three carbonyl Tc 99ms mark | |
| TWI650138B (en) | Multivalent glyco-complex, imaging agent and uses thereof | |
| CN107337681A (en) | A kind of superoxide anion probe and its preparation method and application | |
| CN109438265A (en) | A kind of compound and its preparation method and application with brown adipose tissue with affinity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181009 Termination date: 20190909 |