CN111333638A - 18F-labeled isoquinolino pyridazinone compound and synthesis method and application thereof - Google Patents
18F-labeled isoquinolino pyridazinone compound and synthesis method and application thereof Download PDFInfo
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- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
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- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
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- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract
The invention discloses18The invention discloses an F-labeled isoquinolino pyridazinone compound and a synthesis method and application thereof, belonging to the field of imaging agents18A radioactive isotope of F; prepared by the invention18The F-marked isoquinolin pyridazinone compound has the advantages ofGood myocardial targeting property, and is a myocardial developer with excellent effect.
Description
Technical Field
The invention belongs to the field of imaging agents, and particularly relates to18F-marked isoquinoline pyridazinone compound and a synthesis method and application thereof.
Background
According to the world health organization, American Heart Association andthe national cardiovascular disease center has counted that cardiovascular diseases (CVDs) are the leading cause of death in the world today. SPECT and PET-bearing myocardial perfusion imaging for core cardiology are well established in the American society for cardiology/American Heart Association/American society for Heart diseases (ACC/AHA/ASNC) and other relevant guidelines, and risk stratification of CAD patients can predict the incidence of sudden cardiac death or non-fatal myocardial infarction, reduce the incidence of malignant cardiac events, and thus select appropriate patients for revascularization or drug therapy. The radionuclide myocardial imaging used in clinical practice at present is mainly based on99mSPECT imaging of Tc-MIBI cardionuclide probes is the main.
Compared with SPECT myocardial perfusion imaging, PET myocardial perfusion imaging has the following advantages: (1) the PET has the technical advantages of higher spatial resolution and more accurate attenuation correction, and can accurately detect the existence of the coronary heart disease micro-focus; (2) the amount of imaging agent taken up by the myocardium can be quantitatively determined. Therefore, PET myocardial perfusion imaging has a more promising development prospect than SPECT myocardial perfusion imaging.
Three PET myocardial perfusion imaging agents currently available in clinic, including [ alpha ], [ beta ] -cyclodextrin13N]NH3 (half-life period: 9.97min),82Rb (half-life: 1.27min) and [ 2 ]15O]H2O (half-life: 2.04min) has too short half-life, needs an online cyclotron, and limits the wide clinical application of PET myocardial perfusion imaging because motion load-gated myocardial perfusion imaging cannot be performed. The research and development of novel myocardial perfusion developers are widely concerned by researchers at home and abroad. Wherein the content of the first and second substances,18the physical half-life of F is as long as 109.8min, is more suitable for clinical imaging, is the first nuclide for developing novel PET positron medicines, and is used for developing novel PET positron medicines18F-labeled myocardial perfusion imaging agents are most intensively studied. Is widely reported at present18The F-labeled PET myocardial perfusion imaging agents are mainly divided into two types: (1)18f-labeled pyridazinone compounds; (2)18f-labeled lipophilic cationic compounds such as quaternary ammonium salt and quaternary phosphonium salt compounds. The former has high initial myocardial uptake but poor in vivo and in vitro stability; the latter has poor in vivo and in vitro stability and high bone uptake caused by severe defluorination imaging, and further research is needed. Thus, toSo far as the method for preparing the high-purity sodium silicate,18the F-labeled myocardial perfusion imaging agents are in preclinical research stages, and no medicine is applied clinically through the approval of American FDA or national NMDA. To sum up, a18F-labeled isoquinolino pyridazinone compounds, and a synthesis method and application thereof are to be researched.
Disclosure of Invention
In view of the above problems, the present invention is to provide18F-marked isoquinolino pyridazinone compound, synthesis method and application thereof18The F-marked isoquinoline pyridazinone compound has better myocardial targeting property.
In order to achieve the purpose, the invention adopts the technical scheme that:
18f-marked isoquinoline pyridazinone compound, which has a structural formula as follows:
wherein n is 1-4, X is O or C atom, R1Is a hydrogen atom or an alkyl group, R2Is a halogen atom.
Further, R1The alkyl group in (1) is any of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
Further, R2Is any one of F, Cl and Br.
Further, in the above-mentioned case,18the synthesis method of the F-marked isoquinolin pyridazinone compound comprises the following steps:
(1) taking a compound of formula I and LG- (CH)2-X) n-LG in basic conditions to produce a precursor compound of formula II;
wherein LG is a leaving group LG- (CH)2-X) n-LG wherein n is an integer greater than 0 and X is an O or C atom;
(2) precursor compounds of formula II and18f ionFormation of nucleophilic substitution reaction18F-labeled isoquinolinopyridazinones;
further, the positron nuclide labeling method using nucleophilic substitution reaction is that the compound of the formula II is prepared by heating and reacting for 10-20 minutes under the conditions that a phase transfer reagent K2.2.2 is used as a catalyst and acetonitrile is used as a solvent18F labeled isoquinolinone compounds, and then the purification of the resultant is completed by HPLC.
Further, in the step (1), LG is-OTs or-OTf.
Further, in the above-mentioned case,18the application of the F-labeled isoquinolin pyridazinone compound in a myocardial imaging agent.
Preferably, the first and second liquid crystal materials are,18the synthesis method of the F-marked isoquinolin pyridazinone compound comprises the following steps:
the compound III is used as a raw material, and is butted with ethylene glycol (4-methylzene sulfonate, compound IV) protected by p-toluenesulfonyl in an alkaline condition to generate a precursor compound V for labeling positive electron nuclide.
Precursor compound V and18formation of F ion by reaction18An F-labeled positive electron nuclide probe (Compound VI).
The structural characteristics of the isoquinolin pyridazinone compound and the positron nuclide myocardial imaging agent 18F-flurpirridaz are analyzed, the isoquinolin pyridazinone compound and the positron nuclide myocardial imaging agent are spliced and optimized through the pharmaceutical chemistry principle, and brand new organic micromolecules targeting myocardial mitochondrial membranes are prepared on the basis of not changing the structure of active groups acting on key drugs, and the micromolecules pass through 2 organic moleculesMaking into mitochondria and achieving selective concentration: 1. a positively charged center, which can enter mitochondria through the potential difference between the inner membrane and the outer membrane of the mitochondria (proved by experiments); 2. the parental structure, which possesses flurpirridaz, can selectively bind to mitochondrial complex I by a similar mechanism to flurpirridaz. Through positron nuclide labeling experiment, we successfully label18A radioactive isotope of F. The pharmacological properties of the radioactive marker such as absorption, distribution, metabolism and excretion in vivo are researched through the imaging experiment of normal animals. And a rat myocardial ischemia model is established, and the value of the molecule in evaluating myocardial cell survival is researched through animal experiments.
Through research, it is found that18The F-labeled isoquinoline pyridazinone compound has better cardiac muscle targeting property, and the mechanism is to realize selective concentration on cardiac muscle cell mitochondria through the active transport of the difference between the inner membrane potential and the outer membrane potential of the cardiac muscle mitochondria. Positive electron nuclide myocardial imaging agent18F-flurpirridaz is a mitochondrial complex I inhibitor that achieves selective accumulation of cardiomyocytes by specifically binding to mitochondrial complex I that is abundant in cardiomyocytes.
The invention has the beneficial effects that:
the invention18The F-labeled isoquinoline pyridazinone compound has better myocardial targeting property and can be used as a myocardial developer, and the mechanism is that selective concentration on myocardial cell mitochondria is realized through the active transport of membrane potential difference inside and outside the myocardial mitochondria; at present, no method exists18The isoquinoline pyridazinone myocardial imaging agent has a high heart-liver ratio, can better reflect the function of the heart, has high stability, is clinically applied, and can provide more accurate myocardial function data for cardiac function evaluation.
Drawings
FIG. 1 is a "time-uptake" curve for Compound 12 in different cells;
FIG. 2 is a PET imaging of Compound 12 in normal animals (Wistar rats);
figure 3 is a PET image of compound 12 in an animal model of myocardial ischemia (Wistar rats).
Detailed Description
In order to further illustrate the technical effects of the present invention, the present invention is specifically described below by way of examples.
18The specific preparation method of the F-marked isoquinolin pyridazinone compound comprises the following steps:
dissolving the compound 1N-Boc-4-piperidone (10g, 50mmol) in 80ml of anhydrous toluene, adding p-toluenesulfonic acid monohydrate (0.3g, 1.5mmol) and tetrahydropyrrole (4.3g, 60mmol), heating and refluxing for reaction, separating water generated by the reaction by using an oil-water separator, cooling to room temperature after 3h, adding p-toluenesulfonic acid monohydrate (0.3g, 1.5mmol) and ethyl glyoxylate (50% toluene solution) (11ml, 55mmol), heating and refluxing for 2h, cooling to room temperature, concentrating the reaction solution to about 20ml, slowly dropping 4M hydrochloric acid (54ml) into the solution under vigorous stirring, and continuing stirring at room temperature overnight. Separating an organic phase, extracting a water layer with ethyl acetate for three times, combining the organic layers, washing with saturated salt water once, drying with anhydrous sodium sulfate, filtering, and carrying out silica gel column chromatography purification and separation to obtain 1.5g of the compound 2(E) - (1-tert-butoxycarbonyl-4-oxy-piperidin-3-ylidene) -ethyl acetate, wherein the yield of the two steps is 10.6%; and (Z) - (1-tert-butoxycarbonyl-4-oxy-piperidin-3-ylidene) -acetic acid ethyl ester 4.2g, two-step yield 29.7%.
-:1H NMR(400MHz,CDCl3)δ6.66(t,J＝2.5Hz,1H),4.88(d,J＝2.5Hz,2H),4.24(q,J＝7.2Hz,2H),3.77(t,J＝6.3Hz,2H),2.65(t,J＝6.3Hz,2H),1.48(s,9H),1.32(t,J＝7.1Hz,3H).
-：1HNMR(400MHz,CDCl3)δ7.80(s,1H),4.15(q,J＝7.1Hz,2H),3.99(t,J＝7.4Hz,2H),3.17(d,J＝0.8Hz,2H),2.74–2.35(m,2H),1.54(s,9H),1.26(t,J＝7.1Hz,3H).
The compound 2(E) - (1-tert-butoxycarbonyl-4-oxo-piperidin-3-ylidene) -acetic acid ethyl ester (1.5g, 5.3mmol) was dissolved in 10ml of anhydrous ethanol, tert-butylhydrazine hydrochloride (1.3g, 10.6mmol) and acetic acid (1.3ml) were added, and the mixture was refluxed for 3 hours under heating, and the solvent was dried by spinning and separated by silica gel column chromatography to obtain 1.1g (compound 3) of a pale yellow solid with a yield of 69%.
-：1HNMR(400MHz,CDCl3)δ12.45(s,1H),6.74(d,J＝1.6Hz,1H),4.63(d,J＝6.0Hz,2H),3.70(t,J＝6.1Hz,2H),2.84(t,J＝6.1Hz,2H),1.52(s,9H),1.49(s,9H).
Compound 3(1.0g, 3.3mmol) was dissolved in 8ml dichloromethane and trifluoroacetic acid (2ml) was added dropwise at 0 ℃ to complete the reaction at room temperature for 2h, solvent was dried to give 0.6g crude compound 4 in 90% yield, which was taken to the next reaction without further purification. Dissolving the product compound 4(0.6g, 2.9mmol) in the last step in 30ml of chloroform, adding 4A molecular sieve (5g) and C70(2.4mg, 2.9umol), then charging oxygen into the reaction system for 30 seconds, irradiating under a blue LED lamp for reaction for 3 hours, cooling the reaction liquid to 0 ℃, adding trimethylsilyl cyanide (0.44g, 4.4mmol), raising the temperature to room temperature for reaction for 4 hours, monitoring the reaction completion by TLC, processing the reaction, purifying and separating by silica gel column chromatography to obtain 0.4g compound 5 with the yield of 60%.
-：1H NMR(400MHz,CDCl3)δ6.33(d,J＝8.8Hz,1H),4.31(s,1H),2.47-2.63(m,2H),2.1(t,J＝6.1Hz,2H),1.47(s,9H).
Adding compound 6 o-dimethyl ether (15g, 108mmol) and paraformaldehyde (6.5g, 2155mmol) into a 250ml round-bottomed bottle, cooling to 0 ℃, then slowly dropwise adding a glacial acetic acid solution (31ml) of 33% hydrobromic acid into the reaction system, reacting at room temperature for 20h, and then heating to 65 ℃ for 1 h. The reaction solution cooled to room temperature was poured into ice water, filtered and dried to obtain 22.7g (compound 7) of a white solid in a yield of 65%.
-：1HNMR(400MHz,CDCl3)δ6.78(s,2H),4.57(s,4H),3.87(s,6H).
The compound 71, 2-dibromomethyl-4, 5-phenyl dimethyl ether (600mg, 1.87mmol) and DIPEA (0.31ml, 1.87mmol) are dissolved in 5ml tetrahydrofuran, heated and refluxed for 24h, then 5ml tetrahydrofuran solution of the compound 5(435mg, 1.87mmol) is added to the reaction system, and heating and refluxing are continued for 24 h. After the reaction was complete, the solvent was spin dried and 1: 1 in diethyl ether/methanol, a solid precipitated and was filtered to give 410mg of compound 8 in 60% yield.
-：1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.23(s,1H),7.02(d,J＝8.8Hz,1H),6.88(d,J＝8.8Hz,1H),5.92(s,1H),4.15(t,J＝6.5Hz,2H),3.85(s,6H)，1.9(t,J＝6.5Hz,2H),1.47(s,9H).
Compound 8(500mg, 1.37mmol) was added to a 50ml round-bottomed flask, heated to 170 ℃ and reacted under reduced pressure with an oil pump for 1.5 hours, and purified and separated by silica gel column chromatography to give 310mg of Compound 9 in 65% yield.
-：1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.20(s,1H),7.05(d,J＝8.9Hz,1H),6.98(d,J＝8.9Hz,1H),5.93(s,1H),5.35(s,1H),4.18(t,J＝6.4Hz,2H),3.83(s,3H)，1.9(t,J＝6.4Hz,2H),1.47(s,9H).
Dissolving the compound 9(300mg, 0.85mmol) in 10ml of acetonitrile, adding potassium carbonate (176mg, 1.28mmol) and the compound 10(393mg, 1.02mmol), heating at 70 ℃ for reaction overnight, cooling to room temperature after the reaction is completed, filtering, spin-drying the solvent, and purifying and separating by silica gel column chromatography to obtain 330mg of the compound 11 with a yield of 68%.
-：1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.26(s,1H),7.48(d,J＝8.1Hz,2H),7.41(d,J＝8.1Hz,2H),7.05(d,J＝9.0Hz,1H),6.98(d,J＝9.0Hz,1H),5.90(s,1H),4.42–4.33(m,2H),4.18(t,J＝6.4Hz,2H),4.06(s,3H),3.83–3.75(m,2H),3.83(s,3H),2.33(s,3H),2.06-2.02(m,2H),1.9(t,J＝6.4Hz,2H),1.47(s,9H).
Dissolving compound 9(300mg, 0.85mmol) in 10ml acetonitrile, adding potassium carbonate (176mg, 1.28mmol) and compound 13(237mg, 1.02mmol), heating at 70 deg.C for reaction overnight, cooling to room temperature after reaction is completed, filtering, spin-drying solvent, purifying and separating by silica gel column chromatography to obtain 280mg of compound 14 with yield of 80%.
-：1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.25(s,1H),7.02(d,J＝9.0Hz,1H),6.88(d,J＝9.0Hz,1H),5.93(s,1H),4.20–4.10(m,2H),4.02-4.12(m,4H),3.83(s,3H),1.89-1.95(m,2H),1.52-1.58(m,2H),1.48(s,9H).
Produced by accelerators18The F-HF solution is transported to a shielded hot chamber through a liquid pipeline and is captured by a strong cation exchange column using crown ether (K222-K)2CO3) Eluting 18F ions adsorbed on the cation exchange column into a glass reaction tube by using eluent, and heating to remove H2And O. Compound 11(2mg) was dissolved in 2ml of acetonitrile, and passed through a reaction tube, and reacted at 90 ℃ for 20 minutes. After completion of the reaction, the mixture was diluted with 5ml of a mixture of 30% MeCN and 70% of trifluoroacetic acid in deionized water and separated by HPLC using a chromatographic system: agilent 1100HPLC System, Waters SunAie Prep C185 um (250 x 10mm) column, 30% MeCN-70% H2O (0.1% TFA), 5 ml/min. Around 15 minutes, a radioactive peak appeared, which was collected and subjected to solvent displacement, and MeCN was washed off for use in subsequent experiments.
Cardiomyocyte uptake assay: selecting rat primary myocardial cells, myocardial fibroblasts and H1975 lung cancer cell strains respectively, culturing the cells to a platform stage, collecting, then carrying out resuspension counting, and inoculating the cells in a cell culture plate overnight according to a certain concentration for use in the next stage. The uptake experiments are briefly described as follows: adding a positron marker to be detected, incubating the mixture with cells to different time points, centrifuging the cells, measuring the radioactivity count of the cells and the culture medium by using a gamma counter respectively to obtain the ratio of the radioactive marker taken in by the cells, and drawing a time-radioactivity uptake ratio curve, which is shown in figure 1. This experiment will continue for 2 hours.
As shown in figure 1, compound 12 exhibited a regular, time-dependent, increasing uptake in rat primary cardiomyocytes and gradually reached equilibrium after 90 minutes (the curve flattened out), with a maximum uptake of 2.15%, whereas the tendency of the compound to be taken up in cardiac fibroblasts and H1975 lung cancer cells was less pronounced than in primary cardiomyocytes (probably related to a higher mitochondrial abundance in cardiomyocytes), with uptake rates in these two cells of up to 1.2% and 1.10%, respectively.
Normal rat PET imaging experiment: after the preparation of the positron marker is completed, healthy normal Wistar rats are selected, and after anesthesia by using isoflurane gas, tail vein injection (the maximum injection volume is not more than 1ml) is carried out according to the dose of 0.16mCi/Kg, and Micro PET/CT static scanning is carried out, wherein the scanning time point is 90 minutes.
The PET imaging image of normal rat is shown in FIG. 2, and the drug is concentrated in heart, liver and intestinal tract after 90 minutes of tail vein injection. Wherein, the intake around the heart and the blood pool is low, the property of the heart can be better displayed, and the Standard Uptake Value (SUV) is calculated to be 3.5 by imaging software. The liver is the main metabolic organ of the medicine, so the radioactivity concentration is high, the standard uptake value is 1.2, and the intestinal radioactivity is mainly caused by the liver-intestine circulation; and (3) calculating the SUV of the blood pool by taking the blood intake value in the heart cavity of the left ventricle, wherein the standard intake value is 1.1. Therefore, the compound can better concentrate in cardiac muscle and completely display the heart, meanwhile, the ratio of the myocardial uptake to the liver uptake (the 'heart-liver ratio') and the ratio of the myocardial uptake to the blood pool uptake (the 'heart-blood ratio') are respectively 2.91 and 3.18, and the contrast with surrounding organ tissues can be better proved to be high in selective uptake in the heart, and the compound can be used as a tool for evaluating the myocardial viability.
Myocardial ischemia rat PET imaging experiment: after the preparation of the positron marker was completed, Wistar rats of a myocardial ischemia model were selected, anesthetized with isoflurane gas, and then subjected to tail vein injection (maximum injection volume not more than 1ml) at a dose of 0.16mCi/Kg, and Micro PET/CT static scanning was performed, with the scanning time point also set to 90 minutes.
The PET imaging image of the rat with myocardial ischemia is shown in figure 3, and after 90 minutes of medicine injection into the tail vein, the medicine is also concentrated in the heart, the liver and the intestinal tract. The ingestion around the heart and in the blood pool is low, the heart property can be better displayed, and the SUV of the heart is calculated to be 2.2 through imaging software. The liver is the major metabolic organ for drugs and therefore its concentration of radioactivity is high, while the intestinal radioactivity is mainly due to the liver-intestine circulation. Compared with SUV (3.5) developed from normal rat myocardium, SUV of ischemic myocardium is 2.2, and shows a certain decrease in uptake value. Meanwhile, the imaging range of the myocardium of the model animal is smaller, and the volume of isotope concentration is far smaller than that of the myocardium imaged by PET of a normal animal. During imaging we also observed that at 120 minutes the concentration of radioactivity in the myocardium was much less than in normal animals. In conclusion, compound 12 has a larger difference in imaging parameters between normal animals and myocardial ischemia animals, and can be used as a powerful tool for evaluating myocardial ischemia.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting, and although the technical solutions of the present invention are described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the present invention, which should be covered by the protection scope of the present invention.
Claims (6)
1.18F-labelled isoquinolinopyridazinonesThe compound is characterized in that the structural formula is as follows:
wherein n is 1-4, X is O or C atom, R1Is a hydrogen atom or an alkyl group, R2Is a halogen atom.
2. The compound of claim 1, wherein R is1The alkyl group in (1) is any of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
3. The compound of claim 1, wherein R is2Is any one of F, Cl and Br.
4. A method for the synthesis of a compound according to any one of claims 1 to 3, characterized in that it comprises the following steps:
(1) taking a compound of formula I and LG- (CH)2-X) n-LG in basic conditions to produce a precursor compound of formula II;
wherein LG is a leaving group LG- (CH)2-X) n-LG wherein n is an integer greater than 0 and X is an O or C atom;
(2) precursor compounds of formula II and18nucleophilic substitution of F ion to form18F-labeled isoquinolinopyridazinones;
5. the method of claim 4, wherein in step (1), LG is-OTs or-OTf.
6. The method of claim 118The application of the F-labeled isoquinolin pyridazinone compound in a myocardial imaging agent.
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| CN114989166A (en) * | 2022-06-02 | 2022-09-02 | 中国人民解放军空军军医大学 | Tumor KRAS G12C mutation targeted positron tracer, preparation method and application |
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| CN112250680A (en) * | 2020-10-23 | 2021-01-22 | 四川大学华西医院 | Novel berberine derivative and synthesis method and application thereof |
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| CN114989166A (en) * | 2022-06-02 | 2022-09-02 | 中国人民解放军空军军医大学 | Tumor KRAS G12C mutation targeted positron tracer, preparation method and application |
| CN114989166B (en) * | 2022-06-02 | 2023-10-10 | 中国人民解放军空军军医大学 | Tumor KRAS G12C mutation targeting positron tracer agent, preparation method and application |
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