CN114773179B - Preparation method of compound I liquid composition and application of compound I liquid composition in myocardial metabolism PET imaging - Google Patents
Preparation method of compound I liquid composition and application of compound I liquid composition in myocardial metabolism PET imaging Download PDFInfo
- Publication number
- CN114773179B CN114773179B CN202210717190.3A CN202210717190A CN114773179B CN 114773179 B CN114773179 B CN 114773179B CN 202210717190 A CN202210717190 A CN 202210717190A CN 114773179 B CN114773179 B CN 114773179B
- Authority
- CN
- China
- Prior art keywords
- compound
- tert
- butyl ester
- vitamin
- liquid composition
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 144
- 239000007788 liquid Substances 0.000 title claims abstract description 62
- 239000000203 mixture Substances 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000012879 PET imaging Methods 0.000 title claims abstract description 10
- 230000004060 metabolic process Effects 0.000 title claims description 8
- 230000002107 myocardial effect Effects 0.000 title claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 119
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 53
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 36
- 238000000746 purification Methods 0.000 claims abstract description 36
- 230000000977 initiatory effect Effects 0.000 claims abstract description 31
- 239000002243 precursor Substances 0.000 claims abstract description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000008569 process Effects 0.000 claims abstract description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 9
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 239000012216 imaging agent Substances 0.000 claims abstract description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 138
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 87
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 74
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 69
- 229930003268 Vitamin C Natural products 0.000 claims description 69
- 235000019154 vitamin C Nutrition 0.000 claims description 69
- 239000011718 vitamin C Substances 0.000 claims description 69
- 150000002500 ions Chemical class 0.000 claims description 42
- 229960005219 gentisic acid Drugs 0.000 claims description 37
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 238000004519 manufacturing process Methods 0.000 claims description 19
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 239000013067 intermediate product Substances 0.000 claims description 8
- 230000004913 activation Effects 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims 1
- 238000002372 labelling Methods 0.000 abstract description 17
- 230000008901 benefit Effects 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract 2
- 230000035484 reaction time Effects 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 48
- 239000012071 phase Substances 0.000 description 45
- 235000019441 ethanol Nutrition 0.000 description 37
- 239000000243 solution Substances 0.000 description 35
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 32
- 230000000052 comparative effect Effects 0.000 description 24
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 23
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 23
- 229920000053 polysorbate 80 Polymers 0.000 description 23
- 229940068968 polysorbate 80 Drugs 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- 239000011780 sodium chloride Substances 0.000 description 16
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 238000003384 imaging method Methods 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 238000010828 elution Methods 0.000 description 7
- 125000004185 ester group Chemical group 0.000 description 7
- -1 lithium aluminum hydride Chemical compound 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- 230000002285 radioactive effect Effects 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- RWSXRVCMGQZWBV-PHDIDXHHSA-N L-Glutathione Natural products OC(=O)[C@H](N)CCC(=O)N[C@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-PHDIDXHHSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- AOYNUTHNTBLRMT-SLPGGIOYSA-N 2-deoxy-2-fluoro-aldehydo-D-glucose Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](F)C=O AOYNUTHNTBLRMT-SLPGGIOYSA-N 0.000 description 4
- 238000005349 anion exchange Methods 0.000 description 4
- 230000003471 anti-radiation Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 3
- 229940001584 sodium metabisulfite Drugs 0.000 description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000002739 cryptand Substances 0.000 description 2
- 238000002059 diagnostic imaging Methods 0.000 description 2
- 238000003113 dilution method Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- HMSWAIKSFDFLKN-UHFFFAOYSA-N hexacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC HMSWAIKSFDFLKN-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000010829 isocratic elution Methods 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229960002668 sodium chloride Drugs 0.000 description 2
- BCAGFJXMCZSAHD-UHFFFAOYSA-N 1,2-bis(2-iodoethoxy)ethane Chemical compound ICCOCCOCCI BCAGFJXMCZSAHD-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- CYZINPCDJDJPBH-UHFFFAOYSA-N Cl.C(C)OCCOCC Chemical compound Cl.C(C)OCCOCC CYZINPCDJDJPBH-UHFFFAOYSA-N 0.000 description 1
- 241000083547 Columella Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000003748 differential diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- IWBOPFCKHIJFMS-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl) ether Chemical compound NCCOCCOCCN IWBOPFCKHIJFMS-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000002200 minicolumn purification Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- QVGXLLKOCUKJST-NJFSPNSNSA-N oxygen-18 atom Chemical compound [18O] QVGXLLKOCUKJST-NJFSPNSNSA-N 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 238000003608 radiolysis reaction Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 235000021309 simple sugar Nutrition 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- TZDAOZJWSHBVHY-PDYHCXRVSA-N tert-butyl 2-[(1S,2R)-2-(5-methylsulfonyloxytridecyl)cyclopropyl]acetate Chemical group CCCCCCCCC(CCCC[C@@H]1C[C@H]1CC(=O)OC(C)(C)C)OS(=O)(=O)C TZDAOZJWSHBVHY-PDYHCXRVSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present application provides a PET imaging agent trans-2- (2- (5-fluoro-), [ solution of a salt of a compound of formula (I) or a salt of a compound of formula (II) 18 F]Tridecyl) cyclopropyl) acetic acid (compound I for short) liquid composition preparation method and its use, wherein, utilize high performance liquid chromatography to purify to the crude product comprising compound I; wherein the mobile phase used in the purification step by high performance liquid chromatography comprises ethanol and water. The method has the advantages that through optimizing an experimental process scheme and changing the dosage of a tert-butyl ester precursor of a compound I, the reaction time for reaching the same marking rate is shortened, and the initiation is improved 18 The radioactivity of F ion increases the labeling rate, thus increasing the yield.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of a compound I liquid composition and application of the compound I liquid composition in myocardial metabolism PET imaging.
Background
As the most advanced imaging technology in the field of biomedical engineering at present, the molecular medical imaging technology is a qualitative and quantitative research on cell and molecular level on the biological process in a living body state by applying an imaging method, and is an imaging technology for carrying out real-time, dynamic, in-vivo and non-invasive imaging on the physiological and pathological changes of an organism on the molecular level. It is a key and core technology for researching targeting and specificity molecular probes and therapeutic drugs. The multi-modal molecular imaging technology can realize the advantage complementation of different imaging devices, so that the obtained image result is more accurate and reliable. Clinical practice proves that the multi-modal molecular medical imaging device plays an important role in early diagnosis and early treatment of major diseases, formulation of treatment schemes and verification and evaluation of treatment effects.
Positron Emission Tomography (PET) devices are primarily functional imaging and consist of a PET imaging device and a radiotracer injected into the patient's blood. One commonly used radiotracer is Fluorodeoxyglucose (FDG), a compound synthesized from a simple sugar and a small amount of radioactive fluorine, for human injection 18 F]After FDG, it accumulates in tissues and organs in the body, and at the same time, 18 f decays to emit a positron which undergoes an annihilation reaction producing a pair of oppositely moving photons of 511keV energy. The PET device can detect these photons and record the information of the pair of photons, and the information reduces the position where the positron annihilates in vivo, thereby obtaining 18 F]Distribution of FDG in the human body.
However, the method is not limited to the specific method 18 F-FDG has some limitations in the clinical application of brain tumor imaging using glucose metabolism as an energy substrate, differential diagnosis of tumor and inflammation and the like.
Disclosure of Invention
The application provides a preparation method and application of a compound I for cardiac imaging.
The technical scheme of the application is as follows:
1. a process for the preparation of a liquid composition of compound I,
purifying a crude product containing the compound I by using high performance liquid chromatography; wherein the mobile phase used in the purification step by high performance liquid chromatography comprises ethanol and water;
the compound I is trans-2- (2- (5-fluoro-), [ 2 ] 18 F]Tridecyl) cyclopropyl) acetic acid.
2. The production method according to the above-mentioned item 1,
in the high performance liquid chromatography purification step:
in the mobile phase, the liquid phase is,
the ethanol is 2-5 parts by volume relative to 1 part by volume of water;
preferably, the ethanol is 3 to 4 parts by volume with respect to 1 part by volume of water.
3. The production method according to the above-mentioned item 1,
in the high performance liquid chromatography purification step:
the mobile phase also includes vitamin C.
4. The production method according to the above-mentioned item 3,
in the high performance liquid chromatography purification step:
in the mobile phase, the addition amount of the vitamin C is 0.1mg/mL-10 mg/mL; preferably 0.1mg/mL to 5 mg/mL.
5. The production method according to the above-mentioned item 1,
in the high performance liquid chromatography purification step:
the mobile phase also includes gentisic acid.
6. The production method according to the above-mentioned item 5,
in the high performance liquid chromatography purification step:
in the mobile phase, the addition amount of the gentisic acid is 0.1mg/mL-10 mg/mL; preferably 0.1mg/mL to 5 mg/mL.
7. The production method according to the above-mentioned item 1,
the chromatographic column is a silica gel column, preferably a reversed phase C18 silica gel chromatographic column, and further preferably an Xbridge BEH C18 OBD Prep column;
more preferably, isocratic elution is used, and the elution flow rate of the mobile phase is 3mL/min to 6 mL/min.
8. The production method according to the above-mentioned item 1,
before the high performance liquid chromatography purification step, a nucleophilic substitution reaction step and a tert-butyl ester removal reaction step are also included:
nucleophilic substitution reaction: after activation, the activated 18 Mixing the F ions with a solution containing a tert-butyl ester precursor of the compound I to perform nucleophilic substitution reaction to obtain an intermediate product solution containing the tert-butyl ester of the compound I;
and (3) carrying out tert-butyl ester removal reaction: adding an acid solvent into the intermediate product solution of the tert-butyl ester of the compound I to carry out tert-butyl ester group removal reaction to obtain a product containing the compound I;
the precursor of the tert-butyl ester of the compound I is trans-tert-butyl 2- (2- (5- (methylsulfonyloxy) tridecyl) cyclopropyl) acetate;
the tert-butyl ester of the compound I is trans-2- (2- (5-fluoro-), [ 2 ] 18 F]Tridecyl) cyclopropyl) tert-butyl acetate.
9. The production method according to the above-mentioned item 8,
in the nucleophilic substitution reaction, the reaction mixture is subjected to a nucleophilic substitution reaction,
compound I tert-butyl ester precursor 18 F has an initial activity ratio in the range of (0.2-5): 1;
wherein the weight unit of the tert-butyl ester precursor of the compound I is mg, and the unit of initial activity is Ci.
10. The production method according to the above-mentioned item 9,
the above-mentioned 18 F has an initial activity of 0.09Ci-11Ci, preferably 3.6Ci-11 Ci.
11. The production method according to the above-mentioned item 8,
in the reaction for removing the tert-butyl ester group,
the acid solvent is a mixed system of trifluoroacetic acid and acetonitrile;
preferably, trifluoroacetic acid is 0.4-2 parts by volume relative to 1 part by volume of acetonitrile;
further preferably, trifluoroacetic acid is 0.6 to 1.5 parts by volume relative to 1 part by volume of acetonitrile.
12 the use of a liquid composition of compound i prepared according to the process of any one of claims 1 to 11 in a PET imaging agent for myocardial metabolism.
In addition, the present application provides a liquid composition comprising compound I, the specific scheme is as follows:
1. a liquid composition comprising compound i, wherein the liquid composition further comprises vitamin C and/or gentisic acid;
the compound I is trans-2- (2- (5- (fluoro 2) 18 F]) Tridecyl) cyclopropyl) acetic acid.
2. The liquid composition according to item 1, wherein the ratio of vitamin C concentration (mg/mL)/activity concentration of Compound I (mCi/mL) is in the range of (0.009-0.2): 1.
3. The liquid composition according to the above-mentioned item 2,
the ratio of vitamin C concentration (mg/mL)/activity concentration of compound I (mCi/mL) ranges from (0.009-0.1): 1.
4. The liquid composition according to item 1, wherein the ratio of gentisic acid concentration (mg/mL)/compound I activity concentration (mCi/mL) ranges from (0.009-0.2): 1.
5. The liquid composition according to the item 4,
the ratio of gentisic acid concentration (mg/mL)/activity concentration of compound I (mCi/mL) ranges from (0.009-0.1): 1.
6. The liquid composition of item 1, further comprising polysorbate 80.
7. The liquid composition according to the item 6,
the concentration of the polysorbate 80 is 0.5mg/mL-2 mg/mL.
8. A method of preparing the liquid composition according to any one of claims 1 to 7,
from the purification step, the vitamin C and/or gentisic acid, compound i in ethanol in water is collected to obtain a liquid composition comprising compound i.
9. The method according to the above-mentioned item 8,
mixing vitamin C and/or gentisic acid, sodium chloride and polysorbate 80 with aqueous ethanol solution containing vitamin C and/or gentisic acid and compound I to obtain liquid composition containing compound I.
10. Use of a liquid composition of compound i according to any one of claims 1 to 7, or a liquid composition of compound i prepared by the method of claim 8 or 9, in a PET imaging agent for myocardial metabolism.
Compared with the prior art, the beneficial effect of this application is:
(1) the method shortens the phase of the obtained product by optimizing the experimental process scheme and changing the dosage of the tert-butyl ester precursor of the compound IReaction time for same labeling rate, improved initiation 18 The radioactivity of F ion increases the labeling rate, thus increasing the yield. The process parameters and the process flow are specific and specific, and the method is suitable for large-batch activity production and meets the automation requirement.
(2) In the optimized technical scheme, the anti-radiation decomposition agent is used as the mobile phase in the purification process, so that the product loss caused by radiation decomposition in the purification and prescription processes is avoided, and the yield is improved. In addition, the anti-radiation decomposition agent is used in the prescription process, so that the stability of the product is ensured.
(3) The application optimizes the purification process, removes C18 columella, and adopts ethanol/water system as mobile phase instead of acetonitrile/water system. The time is simplified, and the radiochemical purity and stability of the product are improved.
Detailed Description
The chemical name of the compound I is trans-2- (2- (5- (fluoro 2) 18 F]) Tridecyl) cyclopropyl) acetic acid having the chemical formula:
the chemical formula is: c 18 H 33 18 FO 2
The molecular weight is: 299.46
In the context of the present application, it is, 18 the F-labeled myocardial metabolism PET imaging agent refers to a compound I liquid composition.
A compound I tert-butyl ester precursor is trans-2- (2- (5- (methylsulfonyloxy) tridecyl) cyclopropyl) acetic acid tert-butyl ester, and has a chemical structural formula:
the chemical formula is: c 23 H 44 O 5 S
The molecular weight is: 432.66
The compound I is tert-butyl ester with the chemical name of trans-2-(2- (5-fluoro-) 18 F]Tridecyl) cyclopropyl) tert-butyl acetate having the chemical formula:
the chemical formula is: c 22 H 41 18 FO 2
The molecular weight is: 355.57
Aminopolyethers (K) 222 ) Is a three-bridged crown ether molecule with a cryptic cavity, is a typical aza cryptic ether, and is one of cryptic ethers. The aza-cryptand ether can well select cations for complexing transition metals and heavy metals due to unique coordination characteristics, and the obtained complex is more stable and has lipophilicity and hydrophilicity, so the aza-cryptand ether has better research prospect.
In the prior art, aminopolyethers (K) 222 ) The classical synthesis method is a high dilution method proposed by Lehn and the like, and is one of typical non-template ion synthesis methods, and the specific steps are that raw materials of 1, 8-diamino-3, 6-dioxaoctane and 1, 8-diacid chloride-3, 6-dioxaoctane are dissolved in a large amount of benzene solvent, are heated and react for 8 hours, are reduced for 24 hours through lithium aluminum hydride, and are separated by column chromatography and recrystallized to obtain the aminopolyether (K) 222 ). The method needs a large amount of solvents such as benzene, and has the advantages of long synthetic route, complex operation, low yield and low economic benefit. In addition to the high dilution method, the aminopolyethers (K) 222 ) Another classical synthesis method of (A) is the use of Na as proposed by Kulstad and Malmsten 2 CO 3 Obtaining aminopolyether (K) in acetonitrile by using the same as a template 222 ) Then decomplexed by a resin to obtain the aminopolyether (K) 222 ) The method of (1). The preparation method comprises the specific steps of carrying out reflux reaction on raw materials of 1, 2-di (2-iodoethoxy) ethane and benzylamine in an acetonitrile solution for 3 days, then carrying out post-treatment to obtain an intermediate, recrystallizing the intermediate with acetone, filtering to obtain a NaI complex, and respectively carrying out decomplexation on the NaI complex through cation exchange resin and anion exchange resin under an acidic condition to obtain amino polyether (K) 222 ). The methodSimple equipment, less solvent consumption and mild reaction conditions. However, the applicant has found that the method of decomplexing by ion exchange resin cannot proceed when the content of sodium ions is reduced to a certain amount, and the yield is low.
The application provides a preparation method of a compound I, which comprises the following steps:
the application provides a preparation method of a compound I, which is characterized in that,
purifying a crude product containing the compound I by using high performance liquid chromatography;
wherein the mobile phase used in the purification step by high performance liquid chromatography comprises ethanol and water.
In some embodiments of the present application, in the high performance liquid chromatography purification step: in the mobile phase, the ethanol is 2-5 parts by volume relative to 1 part by volume of water; preferably, the ethanol is 3 to 4 parts by volume with respect to 1 part by volume of water;
for example, the ethanol may be 2 parts by volume, 3 parts by volume, 4 parts by volume, 5 parts by volume, or any range therebetween, relative to 1 part by volume of water.
In some embodiments of the present application, in the high performance liquid chromatography purification step: the mobile phase also includes vitamin C.
In some embodiments of the present application, the vitamin C is added in an amount of 0.1mg/mL to 10mg/mL in the mobile phase; preferably 0.1mg/mL-5 mg/mL;
for example, the vitamin C may be added in an amount of 0.1mg/mL, 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, 6mg/mL, 7mg/mL, 8mg/mL, 9mg/mL, 10mg/mL, or any range therebetween.
In some embodiments of the present application, in the high performance liquid chromatography purification step: the mobile phase also includes gentisic acid.
In some embodiments of the present application, the gentisic acid is added in an amount of 0.1mg/mL to 10mg/mL in the mobile phase; preferably 0.1mg/mL-5 mg/mL;
for example, the gentisic acid may be added in an amount of 0.1mg/mL, 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, 6mg/mL, 7mg/mL, 8mg/mL, 9mg/mL, 10mg/mL, or any range therebetween.
In some embodiments of the present application, both vitamin C and gentisic acid may be contained in the mobile phase, or only one of vitamin C and gentisic acid may be contained.
In some embodiments of the present application, in the step of purifying by high performance liquid chromatography, the column is a silica gel column, preferably a reversed phase C18 silica gel column, and more preferably XBridge BEH C18 OBD Prep column.
In some embodiments of the present application, isocratic elution is used, and the elution flow rate of the mobile phase is 3mL/min to 6 mL/min;
for example, the elution flow rate of the mobile phase may be 3mL/min, 4mL/min, 5mL/min, 6mL/min, or any range therebetween.
In some embodiments of the present application, prior to the step of purifying by high performance liquid chromatography, a nucleophilic substitution reaction step and a tert-butyl ester removal reaction step are further included:
nucleophilic substitution reaction: after activation, the activated 18 Mixing the F ions with a solution containing a tert-butyl ester precursor of the compound I to perform nucleophilic substitution reaction to obtain an intermediate product solution containing the tert-butyl ester of the compound I;
and (3) carrying out tert-butyl ester removal reaction: and (3) adding an acidic solvent into the intermediate product solution of the tert-butyl ester of the compound I to carry out tert-butyl ester group removal reaction to obtain a product containing the compound I.
In some embodiments of the present application, in the nucleophilic substitution reaction,
compound I tert-butyl ester precursor 18 F has an initial activity ratio in the range of (0.2-5): 1;
wherein the weight unit of the tert-butyl ester precursor of the compound I is mg, and the unit of initial activity is Ci;
for example, changeTert-butyl ester precursor of Compound I 18 The F initial activity ratio may be 0.2:1, 0.3:1, 0.5:1, 0.7:1, 1:1, 2:1, 3:1, 4:1, 5:1, or any range therebetween.
In some embodiments of the present application, the 18 F has an initial activity of 0.09Ci-11Ci, preferably 3.6Ci-11 Ci;
for example, the 18 F has an initial activity of 0.09Ci, 0.1Ci, 0.5Ci, 1Ci, 2Ci, 3Ci, 4Ci, 5Ci, 6Ci, 7Ci, 8Ci, 9Ci, 10Ci, 11Ci, or any range therebetween.
In some embodiments herein, the acidic solvent is trifluoroacetic acid with acetonitrile in a tert-butyl ester removal reaction; 0.4 to 2 parts by volume of trifluoroacetic acid to 1 part by volume of acetonitrile; further preferably, trifluoroacetic acid is 0.6-1.5 parts by volume relative to 1 part by volume of acetonitrile;
for example, trifluoroacetic acid is 0.4 parts by volume, 0.5 parts by volume, 0.6 parts by volume, 0.7 parts by volume, 0.8 parts by volume, 0.9 parts by volume, 1 part by volume, 1.5 parts by volume, 2 parts by volume, or any range therebetween, relative to 1 part by volume of acetonitrile.
The present application also provides a liquid composition comprising compound i, wherein the liquid composition further comprises vitamin C and/or gentisic acid.
In some embodiments herein, the ratio of vitamin C concentration (mg/mL)/activity concentration of compound I (mCi/mL) ranges from (0.009-0.2):1, preferably (0.009-0.1): 1;
for example, the ratio of vitamin C concentration (mg/mL)/activity concentration of compound i (mCi/mL) can be 0.009:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, 0.17:1, 0.18:1, 0.19:1, 0.2:1, or any range therebetween.
In some embodiments herein, the ratio of gentisic acid concentration (mg/mL)/activity concentration of compound i (mCi/mL) ranges from (0.009-0.2):1, preferably (0.009-0.1): 1;
for example, the ratio of gentisic acid concentration (mg/mL)/activity concentration of compound i (mCi/mL) may be 0.009:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, 0.17:1, 0.18:1, 0.19:1, 0.2:1 or any range therebetween.
In some embodiments of the present application, vitamin C and gentisic acid may be contained together or only one of vitamin C and gentisic acid may be contained in a liquid composition comprising compound i.
In some embodiments of the present application, the liquid composition further comprises polysorbate 80.
In some embodiments of the present application, the polysorbate 80 concentration is 0.5mg/mL to 2 mg/mL;
for example, the polysorbate 80 concentration may be 0.5mg/mL, 0.8mg/mL, 1mg/mL, 1.5mg/mL, 2mg/mL, or any range therebetween.
The present application also provides a method for preparing the above liquid composition, wherein,
from the purification step, the vitamin C and/or gentisic acid, compound i in ethanol in water is collected to obtain a liquid composition comprising compound i.
In some embodiments of the present application, vitamin C and/or gentisic acid, sodium chloride, polysorbate 80 are mixed with aqueous ethanol containing vitamin C and/or gentisic acid, compound i, to obtain a liquid composition comprising compound i.
The application also provides the application of the compound I liquid composition and the compound I liquid composition prepared by the method in a PET imaging agent for myocardial metabolism.
In the context of the present application, it is, 18 f initial Activity also known as 18 F ion activity, which means that the accelerator is started to generate proton beam to bombard oxygen-containing gas 18 O]After the water is added, the product contains 18 Solution of F ions, measured by activity meter 18 The activity of the F ion.
In the context of the present application, it is, 18 the F start activity is the bombardment of oxygen containing [ alpha ], [ beta ] with a proton beam generated by a start accelerator 18 O]After the water is added, the product contains 18 A solution of F ions is then detectable, i.e. detectable means a reasonable detection time within the grasp of the person skilled in the art, for example within 10 minutes after production. Furthermore, as will be appreciated by those skilled in the art, as the dwell time after production varies, 18 there is some variation in F initial activity, but usually the error range is within. + -. 10%.
In some embodiments of the present application, the 18 F has an initial activity of 0.09Ci-11 Ci; preferably 3.6Ci-11 Ci; for example, 18 the F starting activity can be 0.09Ci, 0.1Ci, 0.5Ci, 1Ci, 2Ci, 3Ci, 4Ci, 5Ci, 6Ci, 8Ci, 9Ci, 10Ci, 11Ci, or any range therebetween.
In this application, bulk refers to high total activity products, and may generally refer to total activity products in excess of 1Ci, i.e., 37 GBq;
high activity concentration products, which may generally refer to activity concentration products in excess of 50mCi/mL, i.e., 1850 MBq/mL.
In this application, mark rate refers to 18 F and the reaction precursor are subjected to a labeling reaction, 18 f replaces a leaving group in the precursor and is converted into a final marked product containing 18 F, the labeling rate is thus defined as the ratio of the activity of the labeled product to the total number of reactions taking place 18 And F activity.
As used herein, yield refers to the activity of the final product compound I liquid composition and 18 f ratio of initial activities.
In some embodiments of the present application, prior to the nucleophilic substitution reaction step, further comprising 18 F, preparing ions; 18 the F ion preparation step further comprises 18 F ion solution preparation, 18 F ion enrichment and elution, 18 F ion activation;
wherein, 18 f, preparing an ion solution: accelerator fabrication 18 F ion solution;
18 f ion enrichment: prepared by the above method 18 Enriching the F ion solution through an anion exchange column;
18 elution of F ions: eluting with catalyst solution of cryptate and alkali metal salt 18 F ions;
18 f, activating ions: drying the solvent by programmed temperature control, nitrogen or other inert gases, activating 18 F ion, to obtain activated 18 And F ions.
In some embodiments of the present application, the method is as follows 18 In the preparation step of the F ion solution, the solution containing 18 Water of O is transported to the target position of the accelerator, the accelerator is started to generate proton beam to bombard 18 Water of O to produce a product containing 18 A solution of F ions.
In some embodiments of the present application, the method is as follows 18 In the F ion enrichment step, the anion exchange column is a Sep-Pak Accell Plus QMA Carbonate Plus Light Cartridge, in particular a tetraalkylammonium salt anion exchange column.
In some embodiments of the present application, the 18 In the step F, in the catalyst solution of cryptate and alkali metal salt, the dosage of cryptate is 5mg-40mg, and the dosage of alkali metal salt is 1.5mg-20 mg; the amount of cryptate in the solution may be 5mg, 8mg, 10mg, 15mg, 20mg, 40mg or any range therebetween; the amount of alkali metal salt in the solution may be 1.5mg, 3mg, 5mg, 10mg, 20mg or any range therebetween.
In some embodiments of the present application, the cryptate is 4,7,13,16,21, 24-hexaoxa-1, 10-diazabicyclo [8, 8-diazabicyclo [ sic ]]Hexacosane (Kryptofix-2.2.2, aminopolyether); the alkali metal salt is K 2 CO 3 、Na 2 CO 3 、Cs 2 CO 3 、KHCO 3 、NaHCO 3 One or more than two of them.
In some embodiments herein, the catalyst solution is selected from mixed solvent systems of acetonitrile and water, wherein the volume ratio of acetonitrile to water is (0.2-10): 1; for example, the volume ratio of acetonitrile to water can be 0.2:1, 1:1, 2:1, 4:1, 7:1, 10:1, or any range therebetween; the volume of the mixed solvent of acetonitrile and water is 0.3mL-2 mL.
In some embodiments of the present application, the method is as follows 18 F ionIn the activation step, the activation temperature is 80-130 ℃;
wherein, the temperature program control comprises the following steps: at the temperature of 100 ℃ and 120 ℃, the positive pressure is 50-200mbar, the vacuum pressure is-20 to-60 mbar, and the evaporation is 60-120 s; at the temperature of 120-; 120 ℃ plus temperature, positive pressure of 50-200mbar, vacuum pressure of-60 to-100 mbar, evaporation for 10-30 s; at the temperature of 100-; 80-100 ℃, the positive pressure is 400-600mbar, the vacuum pressure is-800-1000 mbar, and the evaporation is 100-120 s; 80-100 ℃, the positive pressure of 600-900mbar, the vacuum pressure of-800 to-1000 mbar and the evaporation of 10-20 s.
The reaction with protecting group (such as tert-butyl ester protecting carboxyl, tert-butyloxycarbonyl protecting amino, etc.) is carried out by two-step process.
In this application, fluorine [ alpha ], [ alpha ] and [ alpha ], [ alpha ] a 18 F]The dosage of the ions is increased from 4Ci level to 10Ci level. The preparation method can be suitable for higher 18 The F ion acts as a scalar.
The preparation method of the compound I provided by the application improves the yield to more than 30%, and shortens the production time from about 80min to about 60 min. In the preparation method, the solvent used in the tert-butyl ester removal reaction is acetonitrile, so that the step of removing the solvent by nitrogen can be omitted, and the flow is shortened. The trifluoroacetic acid/acetonitrile system is used in the tert-butyl ester removal reaction, so that the risk of solvent residue in a final product is reduced, and the tert-butyl ester precursor and the tert-butyl ester of the compound I are improved 18 F is the initial activity, so that the conversion rate of the step is improved; the mobile phase ethanol/water mixed solvent system used in the high performance liquid chromatography purification step omits the subsequent steps of enrichment and purification of a C18 small column and elution of absolute ethanol, avoids the radiolysis of the product under high activity, and shortens the preparation process. In addition, the anti-radiation decomposition agent vitamin C is added into the mobile phase, so that the radiation decomposition in the column purification process is avoided.
The materials used in the tests and the test methods are generally and/or specifically described herein, and in the examples below,% means wt%, i.e. percent by weight, unless otherwise specified. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products commercially available, wherein Table 1 is a raw material source used in the examples.
The parameters set in this embodiment are preferred embodiments of the present application, and those skilled in the art can predict that other parameter ranges will also achieve the technical effects described in this application.
Table 1 sources of raw materials used in the examples
Examples
The automation equipment is equipment with the model number of Allinone of the company Tracis. The plant power unit was high purity nitrogen with an injector motorized rotor, a vacuum system could be provided, and an HPLC purification system configured. Because the process uses the automation equipment which is arranged in the ray shielding box, the operation personnel can be protected from radiation damage, the operation dosage is increased, meanwhile, because of the control of the computer, the process steps can be controlled more accurately, the repeatability is higher, and the artificial deviation is reduced.
EXAMPLE 1 preparation of Compound I
1） 18 Preparation of F ion solution
Will contain oxygen 18 O]2g of water is transported to the target site of the accelerator, and the accelerator is activated to generate a proton beam to bombard the oxygen-containing gas 18 O]Water of producing water containing 18 A solution of the F ions in a solvent, 18 f starts activity 4 Ci.
2） 18 Enrichment of F ions
Prepared by the above-mentioned method 18 The solution of F ions is passed through an anion exchange solid phase extraction cartridge (Waters brand QMA cartridge, preferably first 5mL of 0.5mol/L K 2 CO 3 Leaching, leaching with 10mL of water, activating, 18 f ions were enriched onto QMA cartridges.
3） 18 Elution of F ions
Using cryptate and alkali metal salt catalyst solutionsLeaching and eluting 18 F ion into reaction flask, specifically, adding K 222 8mg (dissolved in 0.3mL acetonitrile) with K 2 CO 3 4mg (dissolved in 0.3mL water) was mixed to prepare a mixed solution of acetonitrile and water, and the above QMA cartridge was eluted, K 18 F/K 222 The complex was eluted into the reaction flask.
4） 18 F ion activation
Subjecting the eluted fraction of step 3) 18 F ions are heated in a nitrogen flow program at 100-125 ℃ to blow the solvent to obtain activated 18 And F ions.
5） 18 Nucleophilic substitution of F ion
Adding 1mL acetonitrile solution containing compound I tert-butyl ester precursor in an amount of 3mg and compound I tert-butyl ester precursor in an amount (mg) in a reaction flask 18 F has an initial activity (Ci) of 3mg/4Ci (i.e. 0.75: 1), heating to 120 ℃ under a closed condition, reacting for 10min, and reacting the compound I tert-butyl ester precursor with K 18 F/K 222 Nucleophilic substitution reaction is carried out to obtain an intermediate product containing the compound I tert-butyl ester.
6) Reaction for removing tert-butyl ester group
Adding 1mL of a trifluoroacetic acid and acetonitrile mixed system into the intermediate product containing the tert-butyl ester of the compound I (wherein the volume ratio of the trifluoroacetic acid to the acetonitrile is 1: 1), reacting at 70 ℃ for 2min, removing a tert-butyl ester protecting group to obtain a crude product containing the compound I, and heating under a nitrogen flow to 100 ℃ after the reaction is finished to remove the solvent.
7) Purifying by high performance liquid chromatography
The crude product containing compound i was loaded into the sample loop and purified according to the following chromatographic conditions: obtaining HPLC eluent
A chromatographic column: xbridge BEH C18 OBD Prep column, 130A, 5 μm, 10X 250mm
Mobile phase: a mixed solvent system of ethanol and water, wherein the volume ratio of the ethanol to the water is 3:1, the mobile phase also comprises vitamin C, and the concentration of the vitamin C is 0.5 mg/mL;
flow rate: 5mL/min
A detector: radioactivity detector
The radioactivity signal was monitored and followed, and the major peak of radioactivity for compound I was collected into a transfer vial.
Purifying to obtain the pure compound I.
Example 2
Example 2 differs from example 1 in that: the amount of compound I tert-butyl ester precursor is 6mg and the amount of compound I tert-butyl ester precursor (mg) is used for 18 F initial activity (Ci) of 6mg/4Ci (i.e. 1.5: 1) the other conditions were the same.
Example 3
Example 3 differs from example 1 in that: the amount of the precursor of tert-butyl ester of compound I is 10mg and the amount of the precursor of tert-butyl ester of compound I (mg) is used for determining the status of the patient 18 The initial activity (Ci) of F was 10mg/4Ci (i.e., 2.5: 1), and the rest of the conditions were the same.
Example 4
Example 4 differs from example 3 in that: 18 in the preparation of the F ion solution, 18 f initial activity 6.5Ci, amount of Compound I tert-butyl ester precursor (mg) & lt 18 F has an initial activity (Ci) of 10mg/6.5Ci (i.e., 1.54: 1), and the rest of the conditions are the same.
Example 5
Example 5 differs from example 3 in that: 18 in the preparation of the F ion solution, 18 f initial activity 10Ci, amount (mg) of compound I tert-butyl ester precursor 18 F has an initial activity (Ci) of 10mg/10Ci (i.e., 1: 1), and the rest conditions are the same.
Example 6
Example 6 differs from example 5 in that the reaction for removing tert-butyl ester group has a trifluoroacetic acid to acetonitrile volume ratio of 0.67:1, and the other conditions are the same.
Example 7
Example 7 differs from example 5 in that the reaction for removing tert-butyl ester group has a ratio of trifluoroacetic acid to acetonitrile of 0.43:1 by volume, and the other conditions are the same.
Example 8
Example 8 differs from example 5 in that in the purification by high performance liquid chromatography, the mobile phase: the mixed solvent system of ethanol and water, wherein the volume ratio of the ethanol to the water is 4:1, and the rest conditions are the same.
Example 9
Example 9 differs from example 5 in that in the purification by high performance liquid chromatography, the mobile phase: the mixed solvent system of ethanol and water, wherein the volume ratio of the ethanol to the water is 2:1, and the rest conditions are the same.
Example 10
Example 10 differs from example 5 in that the concentration of vitamin C in the mobile phase was 1mg/mL in the purification by high performance liquid chromatography, and the other conditions were the same.
Example 11
Example 11 differs from example 5 in that the purification by high performance liquid chromatography was carried out under the same conditions except that the concentration of vitamin C in the mobile phase was 5 mg/mL.
Example 12
Example 12 differs from example 5 in that the concentration of vitamin C in the mobile phase was 10mg/mL in the purification by high performance liquid chromatography, and the other conditions were the same.
Example 13
Example 13 differs from example 5 in that the purification by high performance liquid chromatography is carried out without vitamin C in the mobile phase, and the other conditions are the same.
Example 14
Example 14 differs from example 5 in that the mobile phase further contains L-glutathione in the purification by high performance liquid chromatography, and does not contain vitamin C, and the concentration of L-glutathione is 0.5mg/mL, except that the conditions are the same.
Example 15
Example 15 differs from example 5 in that the purification by high performance liquid chromatography is carried out under the same conditions except that the mobile phase further comprises thiourea, the vitamin C is not contained, and the concentration of thiourea is 0.5 mg/mL.
Example 16
Example 16 differs from example 5 in that the volume ratio of trifluoroacetic acid to dichloromethane in the reaction for removing tert-butyl ester group was 0.18:1, and the other conditions were the same.
Example 17
Example 17 differs from example 5 in that the mobile phase further comprises gentisic acid in the purification by high performance liquid chromatography, vitamin C is not contained, the concentration of gentisic acid is 0.5mg/mL, and the other conditions are the same.
Example 18
Example 18 differs from example 5 in that the mobile phase further comprises vitamin C and gentisic acid in the purification by high performance liquid chromatography, the concentration of vitamin C is 0.25mg/mL, the concentration of gentisic acid is 0.25mg/mL, and the other conditions are the same.
Comparative example 1
Comparative example 1 differs from example 5 in that in the purification by high performance liquid chromatography, the mobile phase: the mixed solvent system of acetonitrile and water, wherein the volume ratio of acetonitrile to water is 3:1, and the mobile phase does not contain vitamin C, and the other conditions are the same.
TABLE 2 parameters for examples 1-18 and comparative example 1
In Table 2, wherein the column 1 was Xbridge BEH C18 OBD Prep column, 130A, 5 μm, 10X 250mm, in addition, those shown in Table 2 18 F Start Activity data refers to data detectable after production, but as will be appreciated by those skilled in the art, in general 18 F initial activity varies with standing time and use conditions, and therefore in examples 1-18 and comparative example 1 18 Data on F initial activity are generally targeted 18 Within + -10% of the F starting activity data, all fall within the scope recognized by the skilled person, e.g. 10Ci is targeted 18 F initial activity, which in the actual detection can be 9Ci-11Ci, 1Ci being targeted 18 F initial activity, which in the actual detection can be 0.9Ci-1.1Ci, 4Ci is targeted 18 F StartThe activity, the initial activity in the actual detection, can be 3.6Ci-4.4 Ci.
EXAMPLE 21 Compound I liquid composition
Compound i liquid compositions were formulated from the compound i product of example 1 and collected into a pre-filled transfer bottle. After mixing, the activity concentration of the pure compound I was 2000MBq/mL, i.e., 54 mCi/mL. The prescription in the transfer bottle is mixed with HPLC main peak mobile phase, and the prescription is completed. Specifically, the compound i liquid composition comprises 6.2mg/mL of sodium chloride, 0.88mL/mL of water, 0.12mL/mL of ethanol, 1mg/mL of polysorbate 80, and 0.5mg/mL of vitamin C (wherein the concentration of vitamin C (mg/mL)/the concentration of compound i activity (mCi/mL) is 0.009).
Specifically, the compound I liquid composition of the above-mentioned prescription component is added to an ethanol aqueous solution containing a small amount of vitamin C, compound I so that the concentration of the above-mentioned components satisfies the above-mentioned conditions.
In the compound I liquid composition, absolute ethyl alcohol and polysorbate 80 are used as cosolvent to facilitate the dissolution of the compound I, and vitamin C is used as anti-radiation decomposer to prevent the compound I from being decomposed due to radiation, so that the stability of the compound I is improved.
Example 22
Example 22 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL of sodium chloride, 0.88mL/mL of water, 0.12mL/mL of ethanol, 2mg/mL of polysorbate 80, 0.5mg/mL of vitamin C (wherein the concentration of vitamin C (mg/mL)/the concentration of activity of compound i (mCi/mL) is 0.009), and the rest conditions are the same.
Example 23
Example 23 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL of sodium chloride, 0.88mL/mL of water, 0.12mL/mL of ethanol, 0.5mg/mL of polysorbate 80, 0.5mg/mL of vitamin C (wherein the vitamin C concentration (mg/mL)/the compound i activity concentration (mCi/mL) is 0.009), and the other conditions are the same.
Example 24
Example 24 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL of sodium chloride, 0.88mL/mL of water, 0.12mL/mL of ethanol, 1mg/mL of polysorbate 80, 1mg/mL of vitamin C (wherein the vitamin C concentration (mg/mL)/the compound i activity concentration (mCi/mL) is 0.018), and the other conditions are the same.
Example 25
Example 25 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL sodium chloride, 0.88mL/mL water, 0.12mL/mL ethanol, 1mg/mL polysorbate 80, 5mg/mL vitamin C (wherein the vitamin C concentration (mg/mL)/compound i activity concentration (mCi/mL) is 0.09), and the other conditions are the same.
Example 26
Example 26 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL of sodium chloride, 0.88mL/mL of water, 0.12mL/mL of ethanol, 1mg/mL of polysorbate 80, 10mg/mL of vitamin C (wherein the vitamin C concentration (mg/mL)/the compound i activity concentration (mCi/mL) is 0.18), and the other conditions are the same.
Example 27
Example 27 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL sodium chloride, 0.88mL/mL water, 0.12mL/mL ethanol, 1mg/mL polysorbate 80, 0.5mg/mL gentisic acid (wherein gentisic acid concentration (mg/mL)/compound i activity concentration (mCi/mL) is 0.009).
Specifically, the above-mentioned components are added to an ethanol aqueous solution containing a small amount of gentisic acid and compound i to obtain a compound i liquid composition, so that the concentrations of the above-mentioned components satisfy the above-mentioned conditions.
Comparative example 2
Comparative example 2 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL of sodium chloride, 0.88mL/mL of water, 0.12mL/mL of ethanol, 0.5mg/mL of vitamin C (wherein the concentration of vitamin C (mg/mL)/the concentration of activity of compound i (mCi/mL) is 0.009).
Comparative example 3
Comparative example 3 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL of sodium chloride, 0.88mL/mL of water, 0.12mL/mL of ethanol, 1mg/mL of polyethylene glycol 400, 0.5mg/mL of vitamin C (wherein the concentration of vitamin C (mg/mL)/the concentration of activity of compound i (mCi/mL) is 0.009).
Comparative example 4
Comparative example 4 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL of sodium chloride, 0.88mL/mL of water, 0.12mL/mL of ethanol, 1mg/mL of propylene glycol, 0.5mg/mL of vitamin C (wherein the vitamin C concentration (mg/mL)/the compound i activity concentration (mCi/mL) is 0.009).
Comparative example 5
Comparative example 5 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL of sodium chloride, 0.88mL/mL of water, 0.12mL/mL of ethanol, 1mg/mL of polysorbate 80.
Comparative example 6
Comparative example 6 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL of sodium chloride, 0.88mL/mL of water, 0.12mL/mL of ethanol, 1mg/mL of polysorbate 80, 0.5mg/mL of L-glutathione (wherein the L-glutathione concentration (mg/mL)/the compound i activity concentration (mCi/mL) is 0.009).
Comparative example 7
Comparative example 7 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL of sodium chloride, 0.88mL/mL of water, 0.12mL/mL of ethanol, 1mg/mL of polysorbate 80, 0.5mg/mL of thiourea (wherein the thiourea concentration (mg/mL)/the compound i activity concentration (mCi/mL) is 0.009).
Comparative example 8
Comparative example 8 differs from example 21 in that the compound i liquid composition includes 6.2mg/mL sodium chloride, 0.88mL/mL water, 0.12mL/mL ethanol, 1mg/mL polysorbate 80, 0.5mg/mL sodium metabisulfite (where sodium metabisulfite concentration (mg/mL)/compound i activity concentration (mCi/mL) is 0.009).
TABLE 3 parameters for examples 21 to 27 and comparative examples 2 to 8
Examples of the experiments
The method for measuring the marking rate comprises the following steps: and after the labeling reaction is finished, performing sample injection analysis by using High Performance Liquid Chromatography (HPLC), and determining the ratio of the radioactive peak area of the target product to the peak areas of all radioactive peaks in a liquid chromatogram.
The yield, corrected for decay, was determined by: activity of final liquid composition product measured by activity meter 18 F ratio of initial activities.
The clarity measurement method comprises: and observing the solution to be detected under a clarity detector, comparing the solution with the standard turbidity solution, and judging the clarity of the solution.
The insoluble particles were measured by the following method: and (3) measuring the content of insoluble particles of the solution to be measured by a photoresistance method under an insoluble particle detector, wherein the unit is particle/mL.
The determination method of the radiochemical purity of 0h comprises the following steps: and (4) analyzing by HPLC sample injection to obtain the ratio of the radioactive peak area of the product to the peak areas of all radioactive peaks.
The method for measuring the stability (radiochemical purity index) for 6h comprises the following steps: and (3) after the final product is placed at room temperature for 6h, carrying out sample injection analysis by using HPLC (high performance liquid chromatography), and obtaining the ratio of the radioactive peak area of the product to the peak areas of all radioactive peaks.
TABLE 4 Experimental Effect data for examples 1-18 and comparative example 1
Compared with example 1, examples 2-3 increase the amount of the tert-butyl ester precursor of compound I, which increases both the yield and the labeling rate, and the radiochemical purity is not changed much.
Compared with example 3, in examples 4 and 5, when the amount of the tert-butyl ester precursor of the compound I is constant, the amount is increased 18 The F ion has labeling activity, the yield and the labeling rate do not change greatly, and the radiochemical purity does not change greatly.
Compared with example 5, examples 6 and 7 changed the volume ratio of trifluoroacetic acid to acetonitrile in the step of the tert-butyl ester removal reaction, and as the amount of trifluoroacetic acid was increased, the yield and the labeling rate were increased.
Compared with example 5, the ratio of the ethanol and the water in the mobile phase is changed in examples 8 and 9, the yield and the labeling rate of example 8 are better than those of example 5, the yield and the labeling rate of example 9 are poorer than those of example 5, the peak-out time is faster and the preparation time is shorter when the content of the ethanol in the mobile phase is higher, the yield is increased, but the radiochemical purity is reduced.
Compared with example 5, examples 10-12 changed the content of vitamin C in the mobile phase, and the yield and the labeling rate were increased, and the radiochemical purity was improved.
In examples 13 to 15, when vitamin C was not contained in the mobile phase or was replaced with another substance such as L glutathione or thiourea as compared with example 5, the yield and labeling rate were decreased and the radiochemical purity was lowered.
In example 16, in the step of tert-butyl ester removal reaction, a mixed system of trifluoroacetic acid and dichloromethane was used, and the yield and labeling rate were low, and the radiochemical purity was not high.
Compared with example 5, in examples 17 to 18, the vitamin C was replaced by gentisic acid or a mixture of vitamin C and gentisic acid in the mobile phase, the yield and the labeling rate were equivalent, the radiochemical purity was equivalent, and the effect of gentisic acid in the mobile phase was equivalent to that of vitamin C.
In comparative example 1, the mobile phase used a mixed system of acetonitrile and water, so that the subsequent step of C18 mini-column purification was required, the total preparation time was increased, the yield and labeling rate were low, and the radiochemical purity was not high.
TABLE 5 data of the experimental results of examples 21 to 27 and comparative examples 2 to 8
In examples 21-23, the effect of polysorbate 80 dosage on stability and radiochemical purity was examined, wherein the stability and radiochemical purity of the liquid composition of compound i did not vary much with increasing polysorbate 80.
Examples 24-26 changed the amount of vitamin C compared to example 21, with some improvement in stability and radiochemical purity with increasing vitamin C, and with less change in vitamin C concentration from 1mg/mL to 10 mg/mL. When the vitamin C content is increased, the pH value of the solution is reduced, and the acidity is too high, so that the solution is not beneficial to human health.
As a liquid composition comprising the compound I, trans-2- (2- (5- (fluoro 2;) 18 F]) Tridecyl) cyclopropyl) acetic acid, wherein the liquid is required to be clear and transparent, and the number of insoluble particles with a particle size of 10 μm or more is required to be less than 1200 particles/mL. Compared with example 21, in comparative examples 2-4, after replacing polysorbate 80 with polyethylene glycol 400 or propylene glycol, or when no polysorbate 80 is used, clarity (clearness) and insoluble particles (10 μm or more should be less than 1200 particles/mL) are not satisfied.
In comparative examples 5 to 8, stability and radiochemical purity were reduced when vitamin C was not used or replaced with L-glutathione, thiourea or sodium metabisulfite, as compared with example 21.
In comparison to example 21, in example 27, when vitamin C was replaced with gentisic acid, the stability and radiochemical purity were comparable to example 21, the ability of gentisic acid to stabilize compound I in liquid compositions was comparable.
On the other hand, the radiochemical purity of the compound I is required to be 90% or more, and 90% or less is not suitable, so that the compound I cannot be used.
Although the present disclosure has been described with reference to particular embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present disclosure, and the scope of the present disclosure should be limited only by the terms of the appended claims.
Claims (6)
1. A process for the preparation of a liquid composition of compound I,
purifying the crude product containing the compound I by using a high performance liquid chromatography, and collecting ethanol water solution containing vitamin C and/or gentisic acid and the compound I after purification to obtain a liquid composition containing the compound I;
wherein the mobile phase used in the purification step by high performance liquid chromatography comprises ethanol and water;
the ethanol is 3-5 parts by volume relative to 1 part by volume of water;
the compound I is trans-2- (2- (5-fluoro-), [ 2 ] 18 F]Tridecyl) cyclopropyl) acetic acid;
in the high performance liquid chromatography purification step:
the mobile phase further comprises vitamin C and/or gentisic acid;
the addition amount of the vitamin C is 0.1mg/mL-10 mg/mL;
the addition amount of the gentisic acid is 0.1mg/mL-10 mg/mL;
before the high performance liquid chromatography purification step, a nucleophilic substitution reaction step and a tert-butyl ester removal reaction step are also included:
nucleophilic substitution reaction: after activation, the activated 18 Mixing the F ions with a solution containing a compound I tert-butyl ester precursor, and carrying out nucleophilic substitution reaction to obtain an intermediate product solution containing the compound I tert-butyl ester;
the precursor of the tert-butyl ester of the compound I is trans-tert-butyl 2- (2- (5- (methylsulfonyloxy) tridecyl) cyclopropyl) acetate;
the tert-butyl ester of the compound I is trans-2- (2- (5-fluoro-), [ 2 ] 18 F]Tridecyl) cyclopropyl) tert-butyl acetate;
in a nucleophilic substitution reaction, the compound I tert-butyl ester precursor- 18 F has an initial activity ratio in the range of (0.2-5): 1; wherein the weight unit of the tert-butyl ester precursor of the compound I is mg, and the unit of initial activity is Ci;
the above-mentioned 18 F has an initial activity of 0.09Ci-11 Ci;
and (3) carrying out tert-butyl ester removal reaction: adding an acidic solvent into the intermediate product solution of the tert-butyl ester of the compound I to perform a tert-butyl ester removal reaction to obtain a crude product containing the compound I;
the acid solvent is a mixed system of trifluoroacetic acid and acetonitrile.
2. The production method according to claim 1,
in the mobile phase, the addition amount of the vitamin C is 0.1mg/mL-5 mg/mL.
3. The production method according to claim 1,
in the mobile phase, the addition amount of the gentisic acid is 0.1mg/mL-5 mg/mL.
4. The method according to claim 1, wherein the column is a silica gel column.
5. The production method according to claim 1,
trifluoroacetic acid is 0.4 to 2 parts by volume relative to 1 part by volume of acetonitrile.
6. Use of a liquid composition of compound i prepared according to any one of claims 1 to 5 for the preparation of a PET imaging agent for myocardial metabolism.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210717190.3A CN114773179B (en) | 2022-06-23 | 2022-06-23 | Preparation method of compound I liquid composition and application of compound I liquid composition in myocardial metabolism PET imaging |
| PCT/CN2023/101561 WO2023246830A1 (en) | 2022-06-23 | 2023-06-21 | Method for preparing liquid composition of compound i and use thereof in myocardial metabolism pet imaging |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210717190.3A CN114773179B (en) | 2022-06-23 | 2022-06-23 | Preparation method of compound I liquid composition and application of compound I liquid composition in myocardial metabolism PET imaging |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114773179A CN114773179A (en) | 2022-07-22 |
| CN114773179B true CN114773179B (en) | 2022-09-16 |
Family
ID=82422291
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210717190.3A Active CN114773179B (en) | 2022-06-23 | 2022-06-23 | Preparation method of compound I liquid composition and application of compound I liquid composition in myocardial metabolism PET imaging |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN114773179B (en) |
| WO (1) | WO2023246830A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114773179B (en) * | 2022-06-23 | 2022-09-16 | 北京先通国际医药科技股份有限公司 | Preparation method of compound I liquid composition and application of compound I liquid composition in myocardial metabolism PET imaging |
| CN114796534B (en) * | 2022-06-23 | 2022-09-16 | 北京先通国际医药科技股份有限公司 | Liquid composition containing compound I, preparation method and application |
| CN115947775B (en) * | 2023-03-13 | 2023-06-09 | 北京先通国际医药科技股份有限公司 | Method for preparing compound (I), compound (I) and application thereof |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA05011189A (en) * | 2003-04-17 | 2006-05-25 | Gen Hospital Corp | Method for monitoring blood flow and metabolic uptake in tissue with radiolabeled alkanoic acid. |
| US20100254902A1 (en) * | 2007-11-07 | 2010-10-07 | Jan Van Den Bos | Stabilization of radiopharmaceuticals |
| PT2534136T (en) * | 2010-02-08 | 2017-12-15 | Lantheus Medical Imaging Inc | Methods for synthesizing imaging agents, and intermediates thereof |
| CN107198780A (en) * | 2016-03-18 | 2017-09-26 | 南京江原安迪科正电子研究发展有限公司 | Radiopharmaceutical composition and preparation method thereof, application |
| ES2785173T3 (en) * | 2016-04-07 | 2020-10-06 | Glaxosmithkline Ip No 2 Ltd | Benzo [b] furans as bromodomain inhibitors |
| CN112386949B (en) * | 2020-09-18 | 2022-05-20 | 派特（北京）科技有限公司 | Clinical single-tube fluorine-18 multifunctional module equipment and radiopharmaceutical synthesis process |
| CN112807276B (en) * | 2021-01-26 | 2022-03-01 | 北京先通国际医药科技股份有限公司 | Preparation method and application of pyridazinone myocardial perfusion PET radiopharmaceutical |
| CN114773179B (en) * | 2022-06-23 | 2022-09-16 | 北京先通国际医药科技股份有限公司 | Preparation method of compound I liquid composition and application of compound I liquid composition in myocardial metabolism PET imaging |
-
2022
- 2022-06-23 CN CN202210717190.3A patent/CN114773179B/en active Active
-
2023
- 2023-06-21 WO PCT/CN2023/101561 patent/WO2023246830A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN114773179A (en) | 2022-07-22 |
| WO2023246830A1 (en) | 2023-12-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114773179B (en) | Preparation method of compound I liquid composition and application of compound I liquid composition in myocardial metabolism PET imaging | |
| CN112807276B (en) | Preparation method and application of pyridazinone myocardial perfusion PET radiopharmaceutical | |
| CN114736112A (en) | Preparation method and application of PET imaging agent for myocardial metabolism | |
| CN114835690B (en) | Preparation method of liquid composition containing compound I and application of liquid composition in myocardial perfusion PET imaging | |
| CN109384806B (en) | A [ 2 ]18F]Novel preparation method of FBPA (FBPA) | |
| Velikyan et al. | The importance of high specific radioactivity in the performance of 68Ga-labeled peptide | |
| EP3663307A1 (en) | Production method for radiolabeled aryl compound | |
| CN114796534B (en) | Liquid composition containing compound I, preparation method and application | |
| EP2106808B1 (en) | Radioactive diagnostic imaging agent comprising 1-amino-3-[18f]fluorocyclobutanecarboxylic acid | |
| CN108299482A (en) | F-BPA and its intermediate synthetic method, intermediate and its application | |
| CN114832118B (en) | Compound I liquid composition, preparation method and application thereof | |
| JP5106118B2 (en) | Method for producing radioactive fluorine-labeled organic compound | |
| CN113105432B (en) | Carbon-11 (C)11C) Radiopharmaceutical, preparation method and application thereof | |
| CN107847617B (en) | Metal tricarbonyl complexes containing substituted iminodiacetic acid ligands and their use as radiotracers | |
| CN115724866A (en) | Boron carrier for tumor diagnosis and treatment integration, preparation method and application thereof | |
| CN108358958A (en) | Intermediate, intermediate synthetic method and application | |
| CN108409760A (en) | Intermediate, intermediate synthetic method and application | |
| CN112028914B (en) | A kind of18F-boron trifluoride tyrosine kit and application thereof | |
| RU2301080C1 (en) | Method for preparing 11c -butyrate sodium | |
| BE883304A (en) | COMPLEXES OF TETRASULFONIC PHTHALOCYANIN ACID AND METAL ISOTOPES EMITTING SHORT LIFE GAMMA RADIATIONS AND THEIR APPLICATIONS AS DIAGNOSTIC AGENTS | |
| US20190262479A1 (en) | Imaging method for diffuse intrinsic pontine glioma using an imaging agent, and imaging agents for early stage diagnoses | |
| KR101592291B1 (en) | Method for preparing [18F]Fluoro-L-Dopa with high radiochemical and enantiomeric purity | |
| CN108409759A (en) | Intermediate, intermediate synthetic method and application | |
| CN102757017B (en) | Containing oxygen isotope compound, preparation method, application and composition | |
| Chang et al. | The robotic radiosynthesis of 5-[18F] fluoro-2′-deoxyuridine and its biological characterization |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |