CN101555232A - Pyridazinone compound marked by fluorine-18, preparation method and applications - Google Patents

Pyridazinone compound marked by fluorine-18, preparation method and applications Download PDF

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CN101555232A
CN101555232A CNA2009100845524A CN200910084552A CN101555232A CN 101555232 A CN101555232 A CN 101555232A CN A2009100845524 A CNA2009100845524 A CN A2009100845524A CN 200910084552 A CN200910084552 A CN 200910084552A CN 101555232 A CN101555232 A CN 101555232A
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pnop
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pegn
fpnop
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CN101555232B (en
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张现忠
牟甜甜
杨文江
景慧慧
陆洁
唐志刚
张俊波
王学斌
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BEIJING SHIHONG PHARMACEUTICAL RESEARCH CENTER
Beijing Normal University
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BEIJING SHIHONG PHARMACEUTICAL RESEARCH CENTER
Beijing Normal University
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Abstract

The invention discloses a pyridazinone compound marked by fluorine-18 with a molecular formula of <18>FFPnOP and a preparation method and applications; in the formula, n is equal to 1, 2 or 3. By technical synthesis to ligand OTs-PnOP, the pyridazinone compound <18>FFPnOP marked by radioactive fluorine-18 and stable reference compound <19>FFPnOP are obtained by synthesis, wherein the stable reference compound is used for confirming the structure of the compound with radioactive marks; the compound has high radiochemical purity, good biological properties, high initial uptake value, simple preparation and low use cost, and is applied in the technical fields of radioactive drug chemistry and clinical nuclear medicine as a novel myocardial perfusion imaging agent marked by fluorine-18.

Description

Fluoro-18 pyridazinone compound marked and preparation method and application
Affiliated technical field
The present invention relates to the radiopharmaceutical chemistry and the clinical nuclear medicine technical field of fluoro-18 marks, particularly relate to a class fluoro-18 pyridazinone compound marked and preparation method and application.
Background technology
Coronary heart disease is to threaten one of the most serious disease of human health.In China, evidence of coronary heart diseases and mortality ratio are all in rising trend.2007, the data that the Ministry of Health announces shows: China died from about 3,000,000 people of cardiovascular disorder every year, has become first cause of death of China town and country crowd, accounts for nearly 40% of China resident cause of death.
Myocardial perfusion imaging is used for the heart trouble noninvasive test and starts from the seventies in last century, and its huge diagnostic value worldwide is widely accepted, and becomes one of most important iconography method of present diagnosis of coronary heart disease, therapeutic evaluation and prognosis judgement.Heart muscle perfusion single photon emission computed tomography (SPECT) imaging technique is the current main method that is used for the non-invasive perfusion imaging of coronary heart disease detection clinically.But, to compare with SPECT, positron emission fault (PET) video picture has higher room and time resolving power, can effectively reduce the tissue decay, utilizes the attenuation correction method of organizing of standard can accomplish the absolute quantitation of coronary blood flow.In addition, the short-half-life of positron radionuclide can effectively reduce the radiation dose around the target tissue, and short-half-life also can shorten tranquillization and motion video picture interval.Heart muscle perfusion PET developer commonly used comprises: 15O-H 2O, 13N-NH 3With 82Rb etc.But the above-mentioned developer transformation period is all shorter, and clinical application also is very restricted.And 18F is with respect to other positron radionuclides, and the transformation period is grown (t 1/2=109.8min); Have lower positron energy (512keV), less to the radiation injury of healthy tissues; Its van der Waals radius
Figure A20091008455200051
With hydrogen
Figure A20091008455200052
Similar, can not influence the biological activity of tagged compound, therefore, the myocardial perfusion imaging agent of developing novel fluoro-18 marks has important practical significance.
In the cardiac muscular tissue, mitochondrial weight accounts for 30%.In the overwhelming majority's mammalian tissues, 80%～90% ATP results from Intramitochondrial oxidative phosphorylation process.This process is finished by the respiratory chain that is arranged in mitochondrial inner membrane (electron transport chain).Studies show that: mitochondrial respiratory chain is made up of four kinds of plastosome complex bodys (MC-I, II, III, IV), and wherein MC-I (NADH-ubiquinone oxide-reductase enzyme) is the beginning of this chain.MC-I is a kind of embrane-associated protein that more than 40 different subunits are arranged, and is the entry site of electronics.Several PET myocardial perfusion imaging agents of report are the MC-I inhibitor analogue recently, as 18F-FDHR, 18F-4-(quinazoline derivative), BMS-747158-02 etc.Pyridaben is one of inhibitor of MC-I, how pyridaben is carried out structural modification, be translated into the pyridazinone labelled precursor that can be used for fluoro-18 marks, and the pyridazinone myocardial perfusion imaging agent of preparation fluoro-18 marks is problems that the present technique field need solve.
Summary of the invention
The purpose of this invention is to provide a class radiochemical purity height, good, the initial picked-up value of biological property height, preparation is simple and use cost is low, be applied in fluoro-18 marks in heart muscle perfusion positron emission computerized tomograph field new pyridazinone ([ 18F] FPnOP) compound.
In order to achieve the above object, the present invention is by the following technical solutions: the pyridazinone compound of a class fluoro-18 marks, its molecular formula be [ 18F] FPnOP, its general structure is as follows:
Figure A20091008455200061
Wherein, n=1,2,3.
The preparation method of the pyridazinone compound of fluoro-18 marks is as follows:
(1) part OTs-PnOP's is synthetic:
A. under the ice bath, with an amount of MnO 2Add in an amount of concentrated hydrochloric acid with furfural in batches, 20～100 ℃ of reaction 1～2h, cool overnight, suction filtration, recrystallization obtain mucochloric acid (DCA).
B. under the ice bath, with an amount of mucochloric acid, Na 2CO 3Add in the suitable quantity of water with tertiary butyl hydrazonium salt hydrochlorate, stir 1～3h, suction filtration.Precipitation is added in an amount of benzene and the Glacial acetic acid, and 10～60 ℃ of reaction 3～6h obtain 4,5-dichloro pyridazinone (DCP).
C. with an amount of 4-methyl hydroxybenzoate, K 2CO 3, KI and PEGn (n=1～3) be suspended in an amount of pimelinketone, backflow 12-24h obtains MB-PEGn (n=1～3).PEGn: be ethylene chlorhydrin when n=1; Be the 2-2[-chloroethoxy when n=2] ethanol; Be the 2-2[-2[-chloroethoxy when n=3] oxyethyl group] ethanol.
D. an amount of MB-PEGn (n=1～3), imidazoles, dimethyl tertiary butyl chloride silane are added among an amount of DMF, 50～100 ℃ of reaction 1～5h obtain MSB-PEGn (n=1～3).
E. under the ice bath, an amount of MSB-PEGn (n=1～3), lithium aluminium hydride are added in an amount of anhydrous diethyl ether, 0～50 ℃ is stirred 2～3h, obtains SPE-PEGn (n=1～3).
F. with an amount of 4,5-dichloro pyridazinone, cesium carbonate, SPE-PEGn (n=1～3) add in an amount of dry DMF, and 70～100 ℃ of reaction 12～24h obtain SB-PnOP (n=1～3).
G. tetrahydrofuran solution and the SB-PnOP (n=1～3) with an amount of 1mol/L tetra-n-butyl Neutral ammonium fluoride (TBAF) adds in an amount of tetrahydrofuran (THF), and 10～70 ℃ of reaction 1～2h obtain HB-PnOP (n=1～3).
H. an amount of p-methyl benzene sulfonic chloride, 4-Dimethylamino pyridine, diisopropylethylamine, HB-PnOP (n=1～3) are added to anhydrous CH 2Cl 2In, 5～60 ℃ of reaction 2～4h obtain OTs-PnOP (n=1～3).
Its synthetic route is:
Figure A20091008455200071
(2) [ 19F] FPnOP (n=1～3) synthetic
An amount of OTs-PnOP (n=1～3) and tetra-n-butyl Neutral ammonium fluoride (TBAF) are added in an amount of anhydrous acetonitrile, 70～100 ℃ of reaction 20～60min, obtain [ 19F] FPnOP (n=1～3).
Its synthetic route is:
Figure A20091008455200081
(3) pyridazinone compound of fluoro-18 marks ([ 18F] FPnOP, n=1～3) synthetic
With K 222, K 2CO 3, 18[F] F -And OTs-PnOP (n=1～3) adds in an amount of anhydrous acetonitrile, 70～100 ℃ of reaction 20～60min, obtain [ 18F] FPnOP (n=1～3).
Its synthetic route is:
Above-mentioned described chemosynthesis reagent all is commercial goods, and wide material sources obtain easily.
The present invention is with radioactivity 18[F] F -And OTs-PnOP (n=1～3) prepared in reaction obtain described radioactive fluorine-18 mark pyridazinone compound ([ 18F] FPnOP, n=1～3), be a kind of novel myocardial perfusion imaging agent.[ 18F] radioactive fluoro-18 in FPnOP (n=1～3) molecule, can be used for positron emission computerized tomograph (PET).[ 18F] good, initial picked-up value of radiochemical purity height, biological property and the target to non-target ratio height of FPnOP (n=1～3).Compare with the positron myocardial perfusion imaging agent of having reported, its biological property is better, can become the application clinically of a kind of novel myocardial perfusion imaging agent.
With [ 18F] FP2OP is example, the putting productive rate behind its decay correction is 30～55%, radiochemicsl purity＞99%.
Experiment shows, [ 18F] the basic performance of FP2OP is as follows:
1.[ 18F] FP2OP bio distribution in the normal mouse body
Get 20 normal Kunming small white mouses, in tail vein injection 0.1mL[ 18F] FP2OP (about 0.296MBq).Sacrificed by decapitation behind injection back 2,15,30,60min.Take out tissues such as the heart, liver, lung, kidney, muscle, bone, blood, weighing is also surveyed its radiocounting in gamma counter.[ 18F] bio distribution of FP2OP in normal mouse see Table 1.
Table 1.[ 18F] FP2OP the intravital bio distribution of mouse (%ID/g ± SD, n=5)
Figure A20091008455200091
Bio distribution result's demonstration in normal mouse, [ 18F] FP2OP has very high initial picked-up and certain delay arranged in cardiac muscle.Behind the injection 2min, myocardium picked-up value is (41.90 ± 4.52) %ID/g, and behind the injection 60min, the cardiac muscle picked-up still has (24.80 ± 0.71) %ID/g.Simultaneously, [ 18F] FP2OP target to non-target ratio value is higher, and the conscience ratio is 6.83 during as 2min, and the cardiopulmonary ratio is 9.49, and the painstaking effort ratio is 35.74.No matter it is in cardiac muscle picked-up value, or the target-to-nontarget ratio aspect, [ 18F] FP2OP all is far superior to current at clinical widely used myocardial perfusion imaging agent 99mTc-MIBI, we think that such title complex is expected to develop into the novel myocardial perfusion imaging agent of a class in view of the above.
Embodiment:
During below with n=2 is example, by embodiment in detail the present invention is described in detail: the pyridazinone compound of a class fluoro-18 marks:
(1) part OTs-P2OP's is synthetic:
A. mucochloric acid (DCA) is synthetic
Under the ice bath, in the 1L four-hole bottle, add the 480mL concentrated hydrochloric acid.In the time of 0-10 ℃, add 80g MnO in batches 2, stir, slowly drip the 24g furfural.Behind the stirring at room 30min, slowly be warming up to 60 ℃.In the time of 60～80 ℃, add 42g MnO in batches 2, be warming up to 100 ℃.React become orange clear solution to liquid after, continue reaction 30min, cooling, suction filtration.Precipitation 40mL ether dissolution filters.Filtrate is desolvated through revolving to steam to remove, and with 40mL water recrystallization, obtains the 31g mucochloric acid, is the lightpink tabular crystal.Nuclear magnetic spectrogram: ( 1HNMR, CDCl 3) δ: 6.085 (s, 1H, HO-C-H); ( 13CNMR, CDCl 3) δ: 98.56,123.87,151.25,165.15.Infrared spectrum: (IR)/cm -1: vOH:3407, vC=O:1770, vC=C:1638.
B.4,5-dichloro pyridazinone (DCP) is synthetic
Under the ice bath, the 15g mucochloric acid is dissolved in the 150mL water, adds the 4.5g anhydrous Na 2CO 3, be stirred to the solution becomes clarification.Add 10g tertiary butyl hydrazonium salt hydrochlorate, stir 2.5h, suction filtration.Precipitation with cold water washing after, be transferred to the 100mL eggplant-shape bottle.Add 50mL benzene and 7g Glacial acetic acid, be heated to 35～45 ℃, reaction 4h.Add 20mL water, tell the benzene layer, use 20mL 5%NaOH solution, 20mL 10%HCl solution and 20mL water washing respectively, organic phase is through MgSO 4Drying is revolved to steam and is removed standing over night behind most of solvent.Separate out 6.9g 4, the 5-dichloro pyridazinone is light yellow needle-like crystal.Nuclear magnetic spectrogram: ( 1HNMR, CDCl 3) δ: 1.648 (s, 9H, N (CH 3) 3), 7.729 (s, 1H, N=C-H).Infrared spectrum: (IR)/cm -1: vOH:3461, vC=O:1658.
C.MB-PEG2's is synthetic
With 1g 4-methyl hydroxybenzoate, 1.81g K 2CO 3Add in the 100mL there-necked flask with 0.55g KI.Nitrogen protection adds 20mL pimelinketone and 1.8mL 2-(2-chloroethoxy) ethanol, backflow 24h down.Be cooled to room temperature, suction filtration.After filtrate is revolved steaming, add the 15mL methylene dichloride, suction filtration.Filtrate is revolved and is steamed after 200-300 purpose silicagel column purifying, and developping agent is an ether.Obtain 1.0378g MB-PEG2 at last, be light yellow oil.Nuclear magnetic spectrogram: ( 1HNMR, CDCl 3) δ: 2.072 (s, 1H, OH), 3.677 (t, 2H, CH 2CH 2OH), 3.769 (t, 2H, CH 2CH 2OH), 3.883 (s, 3H, OCH 3), 3.886 (t, 2H, phenyl-O-CH 2CH 2), 4.191 (t, 2H, phenyl-O-CH 2), 6.934 (d, 2H, O-phenyl), 7.986 (d, 2H, CO-phenyl).Infrared spectrum: (IR)/cm -1: vOH:3461, vC=O:1715, vC-O-C:1102.
D.MSB-PEG2's is synthetic
1.0378g MB-PEG2,0.5023g imidazoles, 1.08g dimethyl tertiary butyl chloride silane and 10mL dry DMF are added in the 50mL there-necked flask 80 ℃ of oil bath reaction 4h.Reaction solution dilutes the back suction filtration with the 20mL ethyl acetate.Filtrate is transferred to the 100mL separating funnel, respectively with 20mL washing 5 times, with the saturated NaHCO of 20mL 3Solution is washed 2 times.Organic phase is through MgSO 4After the drying.Suction filtration revolves steaming filtrate and obtains 1.0732g MSB-PEG2, is light yellow oil.Nuclear magnetic spectrogram: ( 1HNMR, CDCl 3) δ: 0.000 (s, 6H, OSi (CH 3) 2), 0.824 (s, 9H, SiC (CH 3) 3), 3.567 (t, 2H, CH 2CH 2OSi), 3.726 (t, 2H, CH 2CH 2OSi), 3.813 (s, 3H, OCH 3), 3.815 (t, 2H, phenyl-O-CH 2CH 2), 4.099 (t, 2H, phenyl-O-CH 2), 6.862 (d, 2H, O-phenyl), 7.911 (d, 2H, CO-phenyl).Infrared spectrum: (IR)/cm -1: vC=O:1723, v=C-O-C:1250, vC-O-C:1087.
E.SPE-PEG2's is synthetic
With 0.28g LiAlH 4Add in the 50mL there-necked flask ice bath 30min.Under the nitrogen protection, add the 8mL anhydrous diethyl ether.1.0732g MBS-PEG2 is dissolved in the 7mL anhydrous diethyl ether, slowly drops in the reaction flask, reaction 2h.Remove ice bath, behind the room temperature reaction 2h, slowly drip the second alcohol and water, do not produce to there being gas.Suction filtration revolves steaming filtrate and obtains 0.38g SPE-PEG, is light yellow oil.Nuclear magnetic spectrogram: ( 1HNMR, CDCl 3) δ: 0.000 (s, 6H, OSi (CH 3) 2), 0.815 (s, 9H, SiC (CH 3) 3), 3.580 (t, 2H, CH 2CH 2OSi), 3.672 (t, 2H, CH 2CH 2OSi), 3.775 (t, 2H, phenyl-O-CH 2CH 2), 4.046 (t, 2H, phenyl-O-CH 2CH 2), 4.466 (s, 2H, CH 2-O-C=C-Cl), 6.807 (d, 2H, O-phenyl), 7.211 (d, 2H, CO-phenyl).
F.SB-P2OP's is synthetic
With 0.38g SPE-PEG2,0.93g DCP, 1.37g Cs 2CO 3Add in the 50mL eggplant-shape bottle 68 ℃ of oil bath reaction 12h with the 10mL dry DMF.Reaction solution is cooled to room temperature, with 20mL ethyl acetate dilution back suction filtration.Filtrate is transferred to the 100mL separating funnel, respectively with 25mL washing 5 times.Organic phase is through MgSO 4Drying is revolved behind the suction filtration and is steamed filtrate, and through 200-300 purpose silicagel column purifying, developping agent is a normal hexane: ethyl acetate=3: 1.Obtain 0.552g SB-P2OP at last, be light yellow oil.Nuclear magnetic spectrogram: ( 1HNMR, CDCl 3) δ: 0.000 (s, 6H, OSi (CH 3) 2), 0.824 (s, 9H, SiC (CH 3) 3), 1.558 (s, 9H, N (CH 3) 3), 3.566 (t, 2H, CH 2CH 2OSi), 3.727 (t, 2H, CH 2CH 2OSi), 3.802 (t, 2H, phenyl-O-CH 2CH 2), 4.057 (t, 2H, phenyl-OCH 2CH 2), 5.177 (s, 2H, CH 2-O-C=C-Cl), 6.876 (d, 2H, O-phenyl), 7.255 (d, 2H, CO-phenyl), 7.663 (s, 1H, N=C-H).Infrared spectrum: (IR)/cm -1: vC=O:1649.
G.HB-P2OP's is synthetic
The tetrahydrofuran solution and the anhydrous THF of 3mL of 0.552g SB-P2OP, 3mL 1mol/L tetra-n-butyl Neutral ammonium fluoride (TBAF) are added in the 25mL eggplant-shape bottle, stir 2h.Reaction solution is transferred in the 100mL separating funnel after diluting with the 20mL ethyl acetate, uses the 20mL water washing.Organic phase MgSO 4Drying is revolved behind the suction filtration and is steamed filtrate, and through 200-300 purpose silicagel column purifying, developping agent is a methylene dichloride: methyl alcohol=7: 1.Obtain 0.361g HB-P2OP at last, be yellow oil.Nuclear magnetic spectrogram: ( 1HNMR, CDCl 3) δ: 1.532 (s, 9H, N (CH 3) 3), 3.586 (t, 2H, CH 2CH 2OH), 3.678 (t, 2H, CH 2CH 2OH), 3.785 (t, 2H, phenyl-O-CH 2CH 2), 4.059 (t, 2H, phenyl-OCH 2CH 2), 5.153 (s, 2H, CH 2-O-C=C-Cl), 6.857 (d, 2H, O-phenyl), 7.240 (d, 2H, CO-phenyl), 7.636 (s, 1H, N=C-H).Infrared spectrum: (IR)/cm -1: vOH:3239 (O-H), vC=O:1643, v=C-O-C:1251, vC-O-C:1137.
H.OTs-P2OP's is synthetic
0.361g HB-P2OP, 0.252g p-methyl benzene sulfonic chloride, 0.167g 4-Dimethylamino pyridine, 0.175g diisopropylethylamine and 3mL anhydrous methylene chloride are added in the 25mL eggplant-shape bottle, stir 2h.Reaction solution is transferred in the 100mL separating funnel after diluting with the 20mL ethyl acetate, respectively with 20mL 0.1M HCl and 20mL washing.Organic phase MgSO 4Drying is revolved behind the suction filtration and is steamed filtrate, and through 200-300 purpose silicagel column purifying, developping agent is a methylene dichloride: methyl alcohol=100: 1.Obtain OTs-P2OP at last, be brown oil.Nuclear magnetic spectrogram: ( 1HNMR, CDCl 3) δ: 1.558 (s, 9H, N (CH 3) 3), 2.341 (s, 3H, phenyl-CH 3), 3.695 (t, 2H, CH 2CH 2OS), 3.729 (t, 2H, CH 2CH 2OS), 3.990 (t, 2H, phenyl-O-CH 2CH 2), 4.122 (t, 2H, phenyl-OCH 2CH 2), 5.180 (s, 2H, CH 2-O-C=C-Cl), 6.850 (d, 2H, O-phenyl), 7.235 (d, 2H, CO-phenyl), 7.265 (d, 2H, phenyl-CH 3), 7.666 (s, 1H, N=C-H), 7.723 (d, 2H, phenyl-SO 3).Infrared spectrum: (IR)/cm -1: vC=O:1652, v=C-O-C:1249, vC-O-C:1092.Mass spectrum: C26H31ClFN2O7S: calculated value: 550.1; Actual value: 551.2.
(2) [ 19F] FP2OP synthetic
The THF solution of 1mL 1mol/L tetra-n-butyl Neutral ammonium fluoride is added in the 25mL eggplant-shape bottle, and 110 ℃ of nitrogen dry up.Adding 1mL anhydrous acetonitrile is evaporated to dried, triplicate.251mg OTs-P2OP is dissolved in the 3mL anhydrous acetonitrile, adds in the reaction flask, backflow 40min.Reaction solution steams except that after desolvating through revolving, and with the dissolving of 15mL methylene dichloride, and is transferred to the 100mL separating funnel, uses the 20mL water washing.Organic phase MgSO 4Drying is revolved behind the suction filtration and is steamed filtrate, and through 200-300 purpose silicagel column purifying, developping agent is a methylene dichloride: methyl alcohol=100: 1.Obtain at last [ 19F] FP2OP, be brown solid.Nuclear magnetic spectrogram: ( 1HNMR, CDCl 3) δ: 1.559 (s, 9H, N (CH 3) 3), 3.759 (dt, 2H, CH 2CH 2OF), 3.835 (t, 2H, phenyl-O-CH 2CH 2), 4.092 (t, 2H, phenyl-OCH 2CH 2), 4.534 (dt, 2H, CH 2CH 2OF), 5.179 (s, 2H, CH 2-O-C=C-Cl), 6.883 (d, 2H, O-phenyl), 7.262 (d, 2H, CO-phenyl), 7.659 (s, 1H, N=C-H); ( 19FNMR, CDCl 3) δ :-222.86.Infrared spectrum: (IR)/cm -1: vC=O:1641, v=C-O-C:1242, vC-O-C:1091.Mass spectrum: C19H24ClFN2O4: calculated value: 398.1; Actual value: 399.1.
(3) pyridazinone compound of fluoro-18 marks ([ 18F] FP2OP) synthetic
1.5mL is contained 6mg K 2CO 3With 11mg K 2.2.2[ 18F] F -Solution adds in the 10mL reaction flask, and 120 ℃ of nitrogen dry up, and adding 0.5mL anhydrous acetonitrile is evaporated to dried, triplicate.2mg OTs-P2OP is dissolved in the 1mL anhydrous acetonitrile, adds in the reaction flask, 90 ℃ of pins reacted 30 minutes.Reaction finishes postcooling to room temperature, is diluted with water to 10mL, adds Sep-Pak C with the 10mL syringe behind the thorough mixing 18The Plus post is used the 10mL water wash.After nitrogen dries up pillar, to another reaction flask, measure the product radioactive activity with the 3mL eluent methylene chloride.
60 ℃ of nitrogen dries up the methylene dichloride in the above-mentioned reaction flask, injects the anti-phase semipreparative column of C-18 (10 * 250mm, Venusil MP-C18, Agela Technologies Inc.) with 0.5mL acetonitrile dissolving back.Collecting retention time is the component of 21.5～22.5min, be [ 18F] FP2OP.The HPLC condition is: A is water mutually, and B is acetonitrile mutually; The drip washing gradient is: 0～5min:95%A, 5.01～8min:95%～60%A, 8.01～25min:60%～10%A, 25.01～40min:10%A; Flow velocity 5mL/min.
Identify by RP-HPLC, [ 18F] retention time of FP2OP is 22.0min, radiochemical purity is greater than 95%.The stable reference compound [ 19F] FP2OP retention time under the same conditions is 21.9min.

Claims (4)

1. the pyridazinone compound of a class fluoro-18 marks, its molecular formula be [ 18F] FPnOP, its general structure is as follows:
Figure A2009100845520002C1
Wherein, n=1,2,3.
2. prepare the preparation method of the pyridazinone compound of a class fluoro-18 marks, its preparation process is as follows:
A. part OTs-PnOP's is synthetic:
A. under the ice bath, with an amount of MnO 2Add in an amount of concentrated hydrochloric acid with furfural in batches, 20～100 ℃ of reaction 1～2h, cool overnight, suction filtration, recrystallization obtains mucochloric acid;
B. under the ice bath, with an amount of mucochloric acid, Na 2CO 3Add in the suitable quantity of water with tertiary butyl hydrazonium salt hydrochlorate, stir 1～3h, suction filtration.Precipitation is added in an amount of benzene and the Glacial acetic acid, and 10～60 ℃ of reaction 3～6h obtain 4, the 5-dichloro pyridazinone;
C. with an amount of 4-methyl hydroxybenzoate, K 2CO 3, KI and PEGn be suspended in an amount of pimelinketone, the 12～24h that refluxes obtains MB-PEGn; PEGn: be ethylene chlorhydrin when n=1; Be 2-[2-chloroethoxy second when n=2] alcohol; Be the 2-2[-2[-chloroethoxy when n=3] oxyethyl group] ethanol;
D. an amount of MB-PEGn, imidazoles, dimethyl tertiary butyl chloride silane are added among an amount of DMF, 50～100 ℃ of reaction 1～5h obtain MSB-PEGn;
E. under the ice bath, an amount of MSB-PEGn, lithium aluminium hydride are added in an amount of anhydrous diethyl ether, 0～50 ℃ is stirred 2～3h, obtains SPE-PEGn;
F. with an amount of 4,5-dichloro pyridazinone, cesium carbonate, SPE-PEGn add in an amount of dry DMF, and 70～100 ℃ of reaction 12～24h obtain SB-PnOP;
G. tetrahydrofuran solution and the SB-PnOP with an amount of 1mol/L tetra-n-butyl Neutral ammonium fluoride adds in an amount of tetrahydrofuran (THF), and 10～70 ℃ of reaction 1～2h obtain HB-PnOP;
H. an amount of p-methyl benzene sulfonic chloride, 4-Dimethylamino pyridine, diisopropylethylamine, HB-PnOP are added to anhydrous CH 2Cl 2In, 5～60 ℃ of reaction 2～4h obtain OTs-PnOP;
Its synthetic route is:
Figure A2009100845520003C1
B.[ 19F] FPnOP synthetic
An amount of OTs-PnOP and tetra-n-butyl Neutral ammonium fluoride are added in an amount of anhydrous acetonitrile, 70～100 ℃ of reaction 20～60min, obtain [ 19F] FPnOP.
Its synthetic route is:
Figure A2009100845520003C2
C. the pyridazinone compound of fluoro-18 marks [ 18F] FPnOP synthetic
With K 222, K 2CO 3, 18[F] F -Add in an amount of anhydrous acetonitrile with OTs-PnOP, 70～100 ℃ of reaction 20～60min, obtain [ 18F] FPnOP.
Its synthetic route is:
Figure A2009100845520004C1
3. the preparation method of the pyridazinone compound of fluoro-18 marks as claimed in claim 2 is characterized in that: the described developed by molecule formula of each step OTs-PnOP, PEGn, SB-PnOP, HB-PnOP, [ 19F] FPnOP and [ 18F] related subscript n=1,2,3 among the FPnOP.
4. a class fluoro-18 pyridazinone compound marked and preparation methods as claimed in claim 1 or 2 is characterized in that: described fluoro-18 is pyridazinone compound marked to be applied in radiopharmaceutical chemistry and the clinical nuclear medicine technical field as myocardial perfusion imaging agent.
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