CN110283222B - Positron imaging agent 18 F-FPGalNAc and preparation method and application thereof - Google Patents
Positron imaging agent 18 F-FPGalNAc and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a positive electron imaging agent 18 The structural formula of the positron imaging agent is as follows:
the positron imaging agent of the invention 18 The F-FPGalNAc contains N-acetylgalactosamine group, the binding affinity of the F-FPGalNAc with ASGPR is much higher than that of galactose group, and the F-FPGalNAc can specifically target tumors such as HepG2, A549, MDA-MB-231, MCF-7, HCT116 and the like with high ASGPR expression and has good imaging effect.
Description
Technical Field
The invention relates to a positive electron developer 18 F-FPGalNAc and a preparation method and application thereof.
Background
Malignant tumors are life and health threatening to humans, so early diagnosis and treatment are of great importance. Anatomical imaging (ultrasound, CT, MRI, etc.) can evaluate tumors from changes in anatomical morphology, such as size, morphology, density, etc., and can provide accurate anatomical information of organs or tissues, and is currently the most commonly used examination method in clinical practice. However, the formation of malignant tumor is a complex process in which mutations of protooncogenes, tumor suppressor genes, genes directly/indirectly controlling cell proliferation, etc. occur, and then changes in molecular level and dysfunction occur, and finally morphological changes occur. Therefore, diagnosis of tumors only from cellular and molecular levels is a true early diagnosis, whereas anatomical imaging does not enable molecular level diagnosis, and is not highly specific and provides limited information for early diagnosis of diseases.
The molecular image can realize real-time, noninvasive and dynamic in-vivo imaging on the molecular level, can discover diseases before the appearance of anatomical morphology change, and hopefully truly realize the early diagnosis and individualized treatment of tumors. The molecular probe is the key of molecular imaging, and is characterized in that special molecules are introduced into a tissue body to be specifically combined with specific molecules (target molecules) to generate signals, and then Magnetic Resonance Imaging (MRI), positron emission computed tomography (PET), CT, Single Photon Emission Computed Tomography (SPECT), ultrasound, optical equipment and the like are adopted for imaging in vitro. In recent years, PET imaging has attracted much attention.
Currently, the most widely used PET imaging agent in clinical practice is 18 F-deoxyglucose (C) 18 F-FDG) is mainly used for identifying benign and malignant tumors of primary tumors, staging malignant tumors, searching primary focuses of tumors, identifying necrosis and residual tumors of tumor tissues after radiotherapy and chemotherapy, diagnosing tumor recurrence, evaluating prognosis of tumor patients, monitoring effects after single chemotherapy or combined therapy and the like. However, 18 F-FDG is a non-tumor specific tracer, and besides physiological uptake of normal tissues, some benign lesions, such as inflammation, active tuberculosis, sarcoidosis, inflammatory pseudotumor, radiotherapy/postoperative reaction and the like can be shown in 18 High uptake of F-FDG leads to false positive results, while some malignancies, such as bronchoalveolar carcinoma, clear cell carcinoma of the kidney, well-differentiated hepatocellular carcinoma, some of the less voluminous and more slowly progressing cancers, show false negatives.
The PET receptor imaging is an imaging technology for displaying the spatial distribution, density and affinity of tumor receptors by utilizing the principle that corresponding ligands marked by positron radioactive nuclide are combined with specific receptors which are highly expressed in tumors and have high affinity with target tissues, has the advantages of high affinity, strong specificity, strong penetrating power, high speed of reaching target points and removing blood by radioactive marked ligands, capability of obtaining images with high contrast between tumors and normal tissues in a short time, almost no occurrence of human immune reaction and the like, has non-invasiveness, can be used for researching the cellular molecule level in the living state, and is one of the important development directions of the current molecular images.
Asialoglycoprotein receptor (ASGPR), also known as hepatic agglutinin, is a receptor discovered in the sixties and seventies of the 20 th century. ASGPR is a transmembrane protein mainly existing on cell surfaces of hepatic sinusoid and basolateral side, and natural ligands of ASGPR are known to be galactose, lactose, N-acetylgalactosamine, asialofetuin, asialoorosomucoid and the like. The research shows that ASGPR is expressed in various tumors, such as MCF-7, A549, HCT116, MDA-MB-231 and the like, and provides a reliable basis for the ASGPR as a target of a PET imaging receptor.
CN 109369755A discloses a positron imaging agent targeting ASGPR 18 F-Gal-1， 18 F-Gal-1 can specifically target tumors such as HepG2, A549, MDA-MB-231, MCF-7 and the like with high ASGPR expression, but 18 The galactose group (Gal) in F-Gal-1 has a general affinity for binding to ASGPR, and 18 F-Gal-1 has small uptake (low target/non-target ratio) and low specificity to lung cancer A549 tumor, which is a problem to be urgently solved in the process of researching ASGPR on tumor uptake at present.
Disclosure of Invention
The invention aims to provide a positron imaging agent 18 F-FPGalNAc and a preparation method and application thereof.
The technical scheme adopted by the invention is as follows:
positron imaging agent 18 F-FPGalNAc, the structural formula is as follows:
the above positron imaging agent 18 The preparation method of the F-FPGalNAc comprises the following steps:
1) dispersing 4-pentyne-1-ol in a solvent, adding triethylamine and 4-dimethylaminopyridine, mixing uniformly, adding p-toluenesulfonyl chloride, reacting sufficiently, extracting a reaction solution, removing water from an extract, distilling under reduced pressure, and separating by column chromatography to obtain the compound I
2) Will be provided with
Dispersing in solvent, adding 18 F ion, fully reacting to obtain
3) Will be provided with
Dispersing in solvent, adding acetic anhydride, and reacting to obtain
4) Will be provided with
Dispersing in solvent, adding 4A molecular sieve, mixing, adding trimethylsilane azide and stannic chloride, reacting, filtering to remove 4A molecular sieve, removing water from the filtrate, distilling under reduced pressure, and separating by column chromatography to obtain the final product
5) Will be provided with
Dispersing in solvent, adding sodium methoxide, full reaction, regulating reactionThe pH value of the solution is 6-7, and the solution is filtered and dried to obtain
6) Will be provided with
Dispersing in solvent, adding
Copper sulfate and sodium ascorbate are fully reacted, the solvent is removed, and the product is washed by water to obtain the positron imaging agent 18 F-FPGalNAc。
Preferably, the positron imaging agent 18 The preparation method of the F-FPGalNAc comprises the following steps:
1) dispersing 4-pentyne-1-ol in a solvent, adding triethylamine and 4-dimethylaminopyridine, uniformly mixing, placing a reaction mixture in an ice bath, dropwise adding tosyl chloride, reacting at normal temperature for 10-20 h after dropwise adding, extracting a reaction solution, removing water from an extract, distilling under reduced pressure, and separating by column chromatography to obtain the compound of formula I
2) Will be provided with
Dispersing in solvent, adding 18 F ions react for 10-15 min at the temperature of 80-90 ℃ to obtain
3) Will be provided with
Dispersing in a solvent, adding acetic anhydride, and reacting at normal temperature for 12-16 h to obtain
4) Will be provided with
Dispersing in a solvent, adding a 4A molecular sieve, uniformly mixing, adding trimethylsilane azide and stannic chloride, reacting at normal temperature for 6-10 h, filtering to remove the 4A molecular sieve, and removing water, distilling under reduced pressure and separating by column chromatography to obtain the final product
5) Will be provided with
Dispersing in a solvent, adding sodium methoxide, reacting at normal temperature for 2-5 h, adjusting the pH value of the reaction solution to 6-7, filtering and drying to obtain the sodium methoxide
6) Will be provided with
Dispersing in solvent, adding
Copper sulfate and sodium ascorbate react for 20-30 min at 40-50 ℃, the solvent is removed, and the product is washed by water to obtain the positron imaging agent 18 F-FPGalNAc。
Preferably, the molar ratio of the 4-pentyne-1-ol, the triethylamine, the 4-dimethylaminopyridine and the p-toluenesulfonyl chloride in the step 1) is 1: (3-7): (0.04-0.09): (1.2-1.8).
Preferably, the solvent in step 1) is dichloromethane.
Preferably, the solvent in step 2) is acetonitrile.
Preferably, the solvent in step 3) is pyridine.
Preferably, step 4) is
The mol ratio of trimethylsilyl azide to tin tetrachloride is 1: (1.2-2.4): (1.6-3.2).
Preferably, the solvent in step 4) is dichloromethane.
Preferably, said step 5) is
The molar ratio of sodium methoxide is 1: (0.3-0.5).
Preferably, the solvent in step 5) is methanol.
Preferably, the pH of the reaction solution is adjusted by a strong acid type cationic resin in step 5).
Preferably, the solvent in step 6) is at least one of water and acetonitrile.
Further preferably, the solvent in step 6) is composed of water and acetonitrile in a mass ratio of 1: 1.
The beneficial effects of the invention are: the positron imaging agent of the invention 18 The F-FPGalNAc contains N-acetylgalactosamine (GalNAc), the binding affinity of the F-FPGalNAc to ASGPR is much higher than that of galactose (Gal), and the F-FPGalNAc can specifically target tumors such as HepG2, A549, MDA-MB-231, MCF-7, HCT116 and the like with high ASGPR expression and has good imaging effect.
1) The positron imaging agent of the invention 18 The N-acetylgalactosamine group (GalNAc) in the F-FPGalNAc is about 50 times higher in binding affinity with ASGPR than the galactose group (Gal) and is stronger in specificity;
2) the positron imaging agent of the invention 18 The F-FPGalNAc has excellent imaging effect on HepG2, A549, MDA-MB-231, MCF-7, HCT116 and other tumors, and particularly has the imaging effect on lung cancer A549 tumor and colon cancer HCT116 tumor models which are obviously better than that of a positron imaging agent 18 F-Gal-1；
3) The positron imaging agent of the invention 18 The yield of the F-FPGalNAc is obviously improved and is higher than that of a positron imaging agent 18 F-Gal-1；
4) The positron imaging agent of the invention 18 F-FPGalNAc also has a certain effect in diagnosing liver cirrhosis diseases of Kunming mice.
Drawings
FIG. 1 is a drawing of 18 Nuclear magnetic fluorine spectrum of F-FPGalNAc.
FIG. 2 is 18 Nuclear magnetic hydrogen spectrum of F-FPGalNAc.
FIG. 3 is a drawing showing 18 Mass Spectrometry (positive ion mode) of F-FPGalNAc.
FIG. 4 is a drawing showing 18 Mass Spectrometry (negative ion mode) of F-FPGalNAc.
FIG. 5 is a drawing showing 18 The PET-CT imaging result of F-FPGalNAc in mouse colon cancer HCT116 tumor model (arrow indicates tumor).
FIG. 6 is a drawing showing 18 PET-CT imaging of F-FDG in the mouse colon cancer HCT116 tumor model (tumor indicated by arrow).
FIG. 7 is a schematic view of 18 The PET-CT imaging result of F-FPGalNAc in a mouse lung cancer A549 tumor model (arrow indicates tumor).
FIG. 8 is a drawing showing 18 The PET-CT imaging result of F-Gal-1 in mouse lung cancer A549 tumor model (arrow indicates tumor).
FIG. 9 is a schematic view of 18 PET-CT imaging results of F-FPGalNAc in a hepatic fibrosis mouse model (15 min, 30min, 60min, 90min and 120min from left to right in sequence).
FIG. 10 is a drawing showing 18 PET-CT imaging results of F-FPGalNAc in a normal mouse model (15 min, 30min, 60min, 90min and 120min from left to right).
FIG. 11 is a schematic view of 18 The biological distribution curve of F-FPGalNAc in the main organs of the liver fibrosis mouse model.
FIG. 12 is a drawing showing 18 The biodistribution curve of F-FPGalNAc in the main organs of a normal mouse model.
Detailed Description
The invention will be further explained and illustrated with reference to specific examples.
Example 1:
positron imaging agent 18 The preparation method of the F-FPGalNAc comprises the following steps:
1) 4-pentyn-1-ol (2.52g, 30mmol) was dispersed in 80mL of dichloromethane, and triethylamine (10.12g, 100mmol) and 4-dimethyl were addedAminopyridine (0.16g, 1.32mmol) and p-toluenesulfonyl chloride (6.86g, 36mmol) are reacted at normal temperature for 14h, ammonium chloride (5.35g, 0.1mol) is added to neutralize triethylamine, extraction is carried out by ethyl acetate, anhydrous sodium sulfate is carried out to remove water, reduced pressure distillation and column chromatography separation are carried out to the extract, and light yellow liquid is obtained
The yield is 83%; 1 H NMR(600MHz,CDCl 3 )δ7.80(d,J＝8.3Hz,2H),7.35(d,J＝8.1Hz,2H),4.15(t,J＝6.1Hz,2H),2.44(d,J＝13.4Hz,3H),2.26(dt,J＝6.9,2.6Hz,2H),1.86(m,2H),1.23(m,1H)；
2) will be provided with
(35.7mg, 0.15mmol) was dispersed in 1mL of acetonitrile, and a further addition was made 18 F ion (100mCi) is reacted for 10min at 85 ℃ to obtain
The yield is 40%;
3) will be provided with
(1g, 4.6mmol) was dispersed in 40mL of pyridine, and acetic anhydride (4.7g, 46mmol) was added thereto to react at room temperature for 12 hours to obtain
The yield is 80%; 1 H NMR(400MHz,CDCl 3 )δ7.27(s,1H),5.72(t,J＝7.7Hz,1H),5.54(d,J＝9.6Hz,1H),5.37(t,J＝4.7Hz,1H),5.10(dd,J＝11.3,3.3Hz,1H),4.44(m,1H),4.11(ddd,J＝8.6,6.0,2.0Hz,1H),4.04(m,1H),2.17(s,3H),2.13(s,3H),2.05(s,3H),2.02(s,3H),1.95(s,3H)；
4) will be provided with
(3.9g, 10mmol) was dispersed in 20mL of ultra dry dichloromethane, an appropriate amount of freshly evaporated 4A molecular sieve was added, stirring was carried out for 20min, trimethylsilane azide (1.38g, 12mmol) and tin tetrachloride (4.16 mmol) were added8g, 16mmol), stirring for 7h at normal temperature, diluting with dichloromethane, vacuum filtering to remove 4A molecular sieve, removing water from filtrate with anhydrous sodium sulfate, vacuum distilling, and separating by column chromatography to obtain white solid crystal
The yield is 59%; 1 H NMR(600MHz,DMSO)δ7.99(d,J＝9.2Hz,1H),5.28(d,J＝2.9Hz,1H),5.00(m,1H),4.73(d,J＝9.3Hz,1H),4.24(t,J＝6.2Hz,1H),4.06(dd,J＝10.6,6.2Hz,2H),3.99(dd,J＝17.5,6.5Hz,1H),2.12(s,3H),2.01(s,3H),1.91(s,3H),1.82(s,3H)；
5) will be provided with
(1g, 2.68mmol) is dispersed in 12mL of methanol, sodium methoxide (43mg, 0.804mmol) is added, stirring is carried out for 2h at normal temperature, the pH value of the reaction solution is adjusted to 6-7 by strong acid type cation resin, filtering and drying are carried out, and white crystals are obtained
The yield is 61%; 1 H NMR(600MHz,DMSO)δ7.74(d,J＝9.0Hz,1H),4.78(d,J＝5.6Hz,1H),4.70(s,1H),4.28(d,J＝9.2Hz,1H),3.87(dd,J＝19.2,9.5Hz,1H),3.70(s,1H),3.47(d,J＝5.6Hz,2H),1.84(s,3H)；
6) will be provided with
(20.5mg, 0.1mmol) was dispersed in 0.4mL of water, 0.3mL of copper sulfate (2.6mg, 0.01mmol) and 0.3mL of sodium ascorbate (4.3mg, 0.02mmol) were added, and 1.0mL of acetonitrile solution dissolved in water was added
(40mCi) reacting at 50 ℃ for 20min, removing the solvent, and washing the product with water to obtain the positron imaging agent 18 F-FPGalNAc, yield 10%.
18 The NMR spectrum of F-FPGalNAc is shown in FIG. 1, the NMR spectrum is shown in FIG. 2 (shift 2.5 is the peak of deuterated DMSO solvent), the mass spectrum (positive ion mode) is shown in FIG. 3, and the mass spectrum is shown inThe spectrum (negative ion mode) is shown in fig. 4.
As can be seen from fig. 1: chemical shift-218.55 ppm, close to the theoretical position of fluoroethyl-218 ppm.
The unscrambling analysis of FIG. 2 is as follows: 1 H NMR(600MHz,DMSO)δ7.90(m,1H),7.74(d,J＝9.4Hz,1H),5.56(d,J＝9.9Hz,1H),4.5(m,1H),4.41(ddt,J＝23.3,19.7,8.0Hz,2H),3.78(d,J＝2.7Hz,1H),3.68(ddd,J＝20.2,12.0,5.3Hz,2H),3.53(m,2H),2.7(t,2H),1.95(m,2H),1.61(m,3H)。
as can be seen from fig. 3: the positive ion mode [ M +1H ] gave 333.12, M-332.12, with a theoretical calculated value of 332.15, which corresponds to the actual value.
As can be seen from fig. 4: the anion mode [ M-1H ] gave 331.10, M332.10 with a theoretical calculated value of 332.15, which corresponds to the actual value.
The results of FIGS. 1 to 4 are summarized as follows: the synthesis is indeed
18 The synthetic route of F-FPGalNAc is as follows:
example 2:
positron imaging agent 18 The preparation method of the F-FPGalNAc comprises the following steps:
1) dispersing 4-pentyne-1-ol (2.52g, 30mmol) in 100mL dichloromethane, adding triethylamine (10.12g, 100mmol), 4-dimethylaminopyridine (0.16g, 1.32mmol) and p-toluenesulfonyl chloride (6.86g, 36mmol), reacting at room temperature for 10h, adding ammonium chloride (5.35g, 0.1mol) to neutralize triethylamine, extracting with ethyl acetate, removing water with anhydrous sodium sulfate, distilling under reduced pressure, and separating by column chromatography to obtain pale yellow liquid
The yield is 74%; 1 H NMR(600MHz,CDCl 3 )δ7.80(d,J＝8.3Hz,2H),7.35(d,J＝8.1Hz,2H),4.15(t,J＝6.1Hz,2H),2.44(d,J＝13.4Hz,3H),2.26(dt,J＝6.9,2.6Hz,2H),1.86(m,2H),1.23(m,1H)；
2) will be provided with
(35.7mg, 0.15mmol) was dispersed in 1mL acetonitrile and added 18 F ion (100mCi) is reacted for 10min at 80 ℃ to obtain
The yield is 30%;
3) will be provided with
(1g, 4.6mmol) was dispersed in 40mL of pyridine, and acetic anhydride (2.35g, 23mmol) was added thereto to react at room temperature for 12 hours to obtain
The yield is 65%; 1 H NMR(400MHz,CDCl 3 )δ7.27(s,1H),5.72(t,J＝7.7Hz,1H),5.54(d,J＝9.6Hz,1H),5.37(t,J＝4.7Hz,1H),5.10(dd,J＝11.3,3.3Hz,1H),4.44(m,1H),4.11(ddd,J＝8.6,6.0,2.0Hz,1H),4.04(m,1H),2.17(s,3H),2.13(s,3H),2.05(s,3H),2.02(s,3H),1.95(s,3H)；
4) will be provided with
(2g, 5mmol) is dispersed in 40mL of ultra-dry dichloromethane, then an appropriate amount of newly evaporated 4A molecular sieve is added, stirring is carried out for 20min, trimethylsilane azide (0.72g, 6.3mmol) and stannic chloride (2.16g, 8.3mmol) are added, stirring is carried out for 10h at normal temperature, dichloromethane is used for dilution, filtration is carried out to remove the 4A molecular sieve, and anhydrous sodium sulfate is carried out on the filtrate to remove water, reduced pressure distillation and column chromatography separation are carried out to obtain white solid crystal
The yield is 59%; 1 H NMR(600MHz,DMSO)δ7.99(d,J＝9.2Hz,1H),5.28(d,J＝2.9Hz,1H),5.00(m,1H),4.73(d,J＝9.3Hz,1H),4.24(t,J＝6.2Hz,1H),4.06(dd,J＝10.6,6.2Hz,2H),3.99(dd,J＝17.5,6.5Hz,1H),2.12(s,3H),2.01(s,3H),1.91(s,3H),1.82(s,3H)；
5) will be provided with
(0.155g, 0.4mmol) in 15mL of methanol, adding sodium methoxide (8mg, 0.15mmol), stirring at room temperature for 2h, adjusting pH of the reaction solution to 6-7 with strong acid type cation resin, filtering, and drying to obtain white crystals
The yield is 61%; 1 H NMR(600MHz,DMSO)δ7.74(d,J＝9.0Hz,1H),4.78(d,J＝5.6Hz,1H),4.70(s,1H),4.28(d,J＝9.2Hz,1H),3.87(dd,J＝19.2,9.5Hz,1H),3.70(s,1H),3.47(d,J＝5.6Hz,2H),1.84(s,3H)；
6) will be provided with
(20.5mg, 0.1mmol) was dispersed in 0.4mL of water, 0.3mL of copper sulfate (2.6mg, 0.01mmol) and 0.3mL of sodium ascorbate (4.3mg, 0.02mmol) were added, and 0.5mL of acetonitrile solution dissolved in water was added
(40mCi) reacting at 50 ℃ for 20min, removing the solvent, and washing the product with water to obtain the positron imaging agent 18 F-FPGalNAc, yield 6%.
Example 3:
positron imaging agent 18 The preparation method of the F-FPGalNAc comprises the following steps:
1) dispersing 4-pentyne-1-ol (2.52g, 30mmol) in 100mL dichloromethane, adding triethylamine (10.12g, 100mmol), 4-dimethylaminopyridine (0.16g, 1.32mmol) and p-toluenesulfonyl chloride (6.86g, 36mmol), reacting at room temperature for 20h, adding ammonium chloride (5.35g, 0.1mol) to neutralize triethylamine, extracting with ethyl acetate, removing water with anhydrous sodium sulfate, distilling under reduced pressure, and separating by column chromatography to obtain pale yellow liquid
The yield is 81%; 1 H NMR(600MHz,CDCl 3 )δ7.80(d,J＝8.3Hz,2H),7.35(d,J＝8.1Hz,2H),4.15(t,J＝6.1Hz,2H),2.44(d,J＝13.4Hz,3H),2.26(dt,J＝6.9,2.6Hz,2H),1.86(m,2H),1.23(m,1H)；
2) will be provided with
(35.7mg, 0.15mmol) was dispersed in 1mL of acetonitrile, and a further addition was made 18 F ion (100mCi) is reacted for 10min at 90 ℃ to obtain
The yield is 35%;
3) will be provided with
(1g, 4.6mmol) was dispersed in 20mL of pyridine, and acetic anhydride (2.7g, 46mmol) was added thereto to react at room temperature for 12 hours to obtain
The yield is 72%; 1 H NMR(400MHz,CDCl 3 )δ7.27(s,1H),5.72(t,J＝7.7Hz,1H),5.54(d,J＝9.6Hz,1H),5.37(t,J＝4.7Hz,1H),5.10(dd,J＝11.3,3.3Hz,1H),4.44(m,1H),4.11(ddd,J＝8.6,6.0,2.0Hz,1H),4.04(m,1H),2.17(s,3H),2.13(s,3H),2.05(s,3H),2.02(s,3H),1.95(s,3H)；
4) will be provided with
(2g, 5mmol) is dispersed in 40mL of ultra-dry dichloromethane, then an appropriate amount of newly evaporated 4A molecular sieve is added, stirring is carried out for 20min, trimethylsilane azide (0.72g, 6.3mmol) and stannic chloride (2.16g, 8.3mmol) are added, stirring is carried out for 10h at normal temperature, dichloromethane is used for dilution, filtration is carried out to remove the 4A molecular sieve, and anhydrous sodium sulfate is carried out on the filtrate to remove water, reduced pressure distillation and column chromatography separation are carried out to obtain white solid crystal
The yield is 59%; 1 H NMR(600MHz,DMSO)δ7.99(d,J＝9.2Hz,1H),5.28(d,J＝2.9Hz,1H),5.00(m,1H),4.73(d,J＝9.3Hz,1H),4.24(t,J＝6.2Hz,1H),4.06(dd,J＝10.6,6.2Hz,2H),3.99(dd,J＝17.5,6.5Hz,1H),2.12(s,3H),2.01(s,3H),1.91(s,3H),1.82(s,3H)；
5) will be provided with
(0.155g, 0.4mmol) in 15mL of methanol, adding sodium methoxide (8mg, 0.15mmol), stirring at room temperature for 2h, adjusting pH of the reaction solution to 6-7 with strong acid type cation resin, filtering, and drying to obtain white crystals
The yield is 61%; 1 H NMR(600MHz,DMSO)δ7.74(d,J＝9.0Hz,1H),4.78(d,J＝5.6Hz,1H),4.70(s,1H),4.28(d,J＝9.2Hz,1H),3.87(dd,J＝19.2,9.5Hz,1H),3.70(s,1H),3.47(d,J＝5.6Hz,2H),1.84(s,3H)；
6) will be provided with
(20.5mg, 0.1mmol) was dispersed in 0.4mL of water, 0.3mL of copper sulfate (2.6mg, 0.01mmol) and 0.3mL of sodium ascorbate (4.3mg, 0.01mmol) were added, and 1.0mL of acetonitrile solution dissolved in water was added
(40mCi) reacting at 50 ℃ for 20min, removing the solvent, and washing the product with water to obtain the positron imaging agent 18 F-FPGalNAc, yield 5%.
Test example:
PET-CT imaging test:
the test method comprises the following steps: injecting the positron imaging agent into a tumor-bearing mouse through a tail vein, metabolizing for 1h, anesthetizing the mouse by using 7% chloral hydrate, fixing the mouse on a scanning bed frame, collecting a PET-CT image of the tumor-bearing mouse, and reconstructing data to obtain a distribution map of the positron imaging agent in the tumor-bearing mouse.
18 The PET-CT imaging result of F-FPGalNAc in mouse colon cancer HCT116 tumor model is shown in FIG. 5Shown in the figure.
18 The PET-CT imaging of F-FDG in mouse colon cancer HCT116 tumor model is shown in FIG. 6.
18 The PET-CT imaging result of F-FPGalNAc in the mouse lung cancer A549 tumor model is shown in figure 7.
18 The PET-CT imaging result of the F-Gal-1 in the mouse lung cancer A549 tumor model is shown in figure 8.
18 The PET-CT imaging result of the F-FPGalNAc in the mouse liver fibrosis model is shown in FIG. 9 (15 min, 30min, 60min, 90min and 120min from left to right).
18 The PET-CT imaging results of F-FPGalNAc in normal mice are shown in FIG. 10 (15 min, 30min, 60min, 90min and 120min from left to right).
18 The biodistribution curve of F-FPGalNAc in the major organs of the mouse liver fibrosis model is shown in FIG. 11.
18 The biodistribution curve of F-FPGalNAc in the major organs of normal mice is shown in FIG. 12.
As can be seen from fig. 5 and 6: 18 F-FPGalNAc was clearly visualized in HCT116 tumors 18 F-FDG was not evident in HCT116 tumors; by delineating the region of interest of the tumor and muscle, the standard Uptake Value (Standardized Uptake Value) of the corresponding region is calculated by software to obtain 18 The standard uptake value of F-FPGalNAc in HCT116 tumor at 60min reaches 2.9% ID/g, and the tumor/muscle is 3.7, which can easily diagnose tumor 18 The standard uptake of F-FDG in HCT116 tumors at 60min is comparable to muscle, and tumors cannot be diagnosed. Therefore, the temperature of the molten metal is controlled, 18 F-FPGalNAc can complement imaging agent 18 F-FDG is not sufficient for diagnosing HCT116 intestinal cancer diseases.
As can be seen from fig. 7 and 8: 18 the F-FPGalNAc is very obvious in the A549 tumor, and 18 F-Gal-1 was not evident in A549 tumors; by delineating the region of interest of the tumor and muscle, the standard uptake value (standard U) of the corresponding region is calculated by softwareptake Value) to yield 18 The standard uptake value of F-FPGalNAc in A549 tumor at 60min reaches 1.2% ID/g, and tumor/muscle is 3.2, so that tumor can be easily diagnosed, and 18 the standard uptake value of F-Gal-1 in A549 tumor at 60min is equivalent to muscle, and the tumor cannot be diagnosed. Therefore, the temperature of the molten metal is controlled, 18 F-FPGalNAc can complement imaging agent 18 F-Gal-1 is poorly diagnosed with A549 lung cancer disease.
As can be seen from fig. 9 and 10: 18 the F-FPGalNAc has clear liver imaging of the whole mouse, can be clearly imaged within 30min and can last for 120min, and is very suitable for liver imaging; liver of liver fibrosis mouse 18 The uptake of F-FPGalNAc was lower than that of normal mice, and there was a significant uneven uptake.
As can be seen from fig. 11 and 12: in the process of kidney metabolism of liver fibrosis mice, the kidney pair 18 The intake of F-FPGalNAc reaches the maximum value within 15min, while the intake reaches the maximum value within 35min in the kidney metabolism process of normal mice, so that under the condition that the liver metabolism system of the mice is damaged, 18 the pharmacokinetics of F-FPGalNAc in the body is changed, and the damage to the liver can cause the increase of the metabolic load of the kidney and lead the time of the maximum value of the kidney metabolism to be advanced. Therefore, the first and second electrodes are formed on the substrate, 18 the F-FPGalNAc can be used for evaluating the overall function of the liver, and can be combined with three-dimensional simulation software to evaluate the function of the residual liver so as to provide assistance for hepatectomy.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. Positron imaging agent 18 F-FPGalNAc, characterized in that: the structural formula is as follows:
2. the positron imaging agent of claim 1 18 The preparation method of F-FPGalNAc is characterized in that: the method comprises the following steps:
1) dispersing 4-pentyne-1-ol in a solvent, adding triethylamine and 4-dimethylaminopyridine, mixing uniformly, adding p-toluenesulfonyl chloride, reacting sufficiently, extracting a reaction solution, removing water from an extract, distilling under reduced pressure, and separating by column chromatography to obtain the compound I
2) Will be provided with
Dispersing in solvent, adding 18 F ion, and fully reacting to obtain
3) Will be provided with
Dispersing in solvent, adding acetic anhydride, and reacting to obtain
4) Will be provided with
Dispersing in solvent, adding 4A molecular sieve, mixing, adding trimethylsilane azide and stannic chloride, reacting, filtering to remove 4A molecular sieve, removing water, distilling under reduced pressure, and separating by column chromatography to obtain the final product
5) Will be provided with
Dispersing in a solvent, adding sodium methoxide, fully reacting, adjusting the pH value of the reaction solution to 6-7, filtering and drying to obtain
6) Will be provided with
Dispersing in solvent, adding
Copper sulfate and sodium ascorbate react fully, the solvent is removed, and the product is washed by water to obtain the positron imaging agent 18 F-FPGalNAc。
3. The method of claim 2, wherein: the mol ratio of the 4-pentyne-1-ol, the triethylamine, the 4-dimethylaminopyridine and the p-toluenesulfonyl chloride in the step 1) is 1: (3-7): (0.04-0.09): (1.2-1.8).
4. The production method according to claim 2 or 3, characterized in that: the reaction in the step 1) is carried out at normal temperature, and the reaction time is 10-20 h; and 2) carrying out the reaction at 80-90 ℃, wherein the reaction time is 10-15 min.
5. The method of claim 2, wherein: and 3) carrying out the reaction at normal temperature for 12-16 h.
6. The method of claim 2, wherein: step 4) the
The mol ratio of trimethylsilyl azide to tin tetrachloride is 1: (1.2-2.4): (1.6-3.2).
7. The production method according to claim 2 or 6, characterized in that: the reaction in the step 4) is carried out at normal temperature, and the reaction time is 6-10 h; and 5) carrying out the reaction at normal temperature for 2-5 h.
8. The production method according to claim 2, characterized in that: step 5) the
The molar ratio of sodium methoxide is 1: (0.3-0.5).
9. The production method according to claim 2, characterized in that: and 6) carrying out the reaction at 40-50 ℃ for 20-30 min.
10. The positron imaging agent of claim 1 18 The application of F-FPGalNAc in preparing a lung cancer PET imaging agent or a colon cancer PET imaging agent.
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