WO2022114333A1 - Procédé de production efficace de 2-[18f]fluoro-4-boronophénylalanine comprenant des isotopes radioactifs - Google Patents

Procédé de production efficace de 2-[18f]fluoro-4-boronophénylalanine comprenant des isotopes radioactifs Download PDF

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WO2022114333A1
WO2022114333A1 PCT/KR2020/017310 KR2020017310W WO2022114333A1 WO 2022114333 A1 WO2022114333 A1 WO 2022114333A1 KR 2020017310 W KR2020017310 W KR 2020017310W WO 2022114333 A1 WO2022114333 A1 WO 2022114333A1
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이상윤
김우경
정준영
이도타츠오
이지혜
알람모하마드막수드
이학정
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가천대학교 산학협력단
(의료)길의료재단
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • Nuclear medicine imaging technology a molecular imaging technology that can sensitively quantify the presence or progression of a disease by acquiring biochemical changes in the body in real time, is very useful.
  • [ 18 F]FDG D-2-deoxy-2-fluoro-glucose
  • [ 18 F]FDG D-2-deoxy-2-fluoro-glucose
  • a basic limitation of glucose metabolizing PET is that tumors of some organs are indistinguishable from normal cells, which significantly reduces the accuracy of diagnosis.
  • tumor cells and normal cells appear almost identical.
  • lung cancer, liver cancer, and prostate cancer have very low tumor contrast in glucose metabolism, and many researchers have attempted to develop new PET radiopharmaceuticals to overcome these limitations.
  • [ 18 F]FBPA shows a high tumor uptake rate based on amino acid uptake and is known as a derivative of phenylalanine, one of the essential amino acids. It is also a derivative of L-boronophenylalanine (L-BPA) used in boron neutron capture therapy (BNCT) as a structure containing a boric acid functional group.
  • L-BPA L-boronophenylalanine
  • BNCT boron neutron capture therapy
  • L-BPA was first introduced in the 1970s and [ 18 F ] FBPA in the late 1990s, and many researchers conducted preclinical and clinical PET studies. There is a problem in that it is necessary to break away from the conventional synthesis method and introduce a synthesis method using the [ 18 F]F anion.
  • the advantage of the electrophilic substitution reaction is that it is easy to obtain a precursor (a reactive material for labeling a radioisotope), and the synthesis process of the reaction is simple.
  • the production of [ 18 F]F 2 gas for commercial purposes has disadvantages in that it is difficult to install and operate a facility, has a very low specific radioactivity characteristic, and is difficult to apply to high radioactivity production.
  • Another object of the present invention is to provide a method for preparing the precursor.
  • step 2 preparing a compound represented by formula 4 from the compound represented by formula 3 prepared in step 1 (step 2);
  • It provides a method for preparing a compound containing a radioactive isotope represented by Formula 1, including; preparing a compound represented by Formula 1 from the compound represented by Formula 4 prepared in Step 2 (step 3). :
  • R 4 and R 5 are each independently —H, halogen, unsubstituted or one or more halogen-substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, unsubstituted or substituted C 6-10 aryl, or R 4 and R 5 are linked to each other ego,
  • R 6 and R 7 are each independently —H, halogen, unsubstituted or substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, or R 6 and R 7 is a 3 to 15 membered cycloalkyl formed by connecting to each other,
  • the substituted C 6-10 aryl is C 1-5 straight or branched chain alkyl, C 1-5 straight or branched chain alkylcarbonyl, and at least one heteroatom selected from the group consisting of N, O and S one or more substituents selected from the group consisting of 5 to 6 membered heteroaryl including substituted C 6-10 aryl ;
  • Y is -H, halogen, -N 2 + , -NO 2 , -CN, straight -chain or branched C 1-5 alkoxy ;
  • R 1 and R 2 are each independently —H, or t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2- an amine protecting group selected from the group consisting of trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc);
  • R 3 is hydrogen, a linear or branched C 1-10 alkyl , or a phenyl substituted with a straight or branched C 1-10 alkyl).
  • Another aspect of the present invention provides a compound represented by the following formula (2), a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof:
  • the method for synthesizing [ 18 F]FBPA uses a nucleophilic substitution reaction using [ 18 F]F anion to overcome the disadvantages of the existing electrophilic substitution reaction to effectively produce [ 18 ] in high yield.
  • F]FBPA was synthesized.
  • HVI hypervalent iodine ylide
  • the method of the present invention enables the mass production of [ 18 F]FBPA using an automatic synthesis device under GMP manufacturing conditions, so it is difficult to diagnose cancer with [ 18 F]FDG, patients who want to predict BNCT treatment, or cancer treatment. It will be very useful when trying to determine the prognosis.
  • TEAB tetraethylammonium bicarbonate
  • FIG. 5 is a diagram showing the results of measuring the radiochemical purity of the FBPA standard sample and the purified [ 18 F]FBPA solution using HPLC.
  • FIG. 6 is a view showing the results of HPLC analysis by mixing the synthesized [ 18 F]FBPA solution and FBPA standard sample.
  • FIG. 7 is a view showing a measurement result of specific radioactivity using a quantitative line of a standard sample.
  • FIG 8 is a diagram showing an efficient three-step label synthesis process of [ 18 F]FBPA provided in one aspect of the present invention.
  • FIG. 10 is a view showing the results of chiral HPLC analysis of Compound A-3 prepared according to step 3 of Example 1 below.
  • FIG. 11 is a view showing the results of chiral HPLC analysis of Compound A-4 prepared according to step 4 of Example 1 below.
  • FIG. 12 is a view showing the results of chiral HPLC analysis of Compound A-5 prepared according to step 5 of Example 1 below.
  • FIG. 13 is a view showing the results of chiral HPLC analysis of Compound A-6 prepared according to step 6 of Example 1 below.
  • FIG. 14 is a view showing the results of chiral HPLC analysis of Compound A ([ 18 F]FBPA) prepared according to step 7 of Example 1 below.
  • [ 18 F]FBPA is a derivative used in boron neutron capture therapy (BNCT), and studies have shown that the intake of L-BPA administered to patients in BNCT can be predicted with PET. It has been reported, and it has recently attracted attention in that it is a method that can confirm the results of brain tumor diagnosis and treatment earlier than MRI.
  • the conventional electrophilic substitution reaction for synthesizing [ 18 F]FBPA has the advantage of being easy to secure a precursor, but has the disadvantages of low specific activity and difficulty in mass production.
  • one aspect of the present invention proposes a hypervalent iodine ylide (HVI) leaving group of a precursor as an effective method for synthesizing [ 18 F]FBPA in high yield in order to solve the above problem.
  • HVI hypervalent iodine ylide
  • the specific activity described in the specification of the present invention refers to the radioactivity per unit mass of a material having a radioactive isotope, and refers to a value obtained by dividing the radioactivity intensity of a specific material by its mass.
  • One aspect of the present invention is
  • step 2 preparing a compound represented by formula 4 from the compound represented by formula 3 prepared in step 1 (step 2);
  • It provides a method for preparing a compound containing a radioactive isotope represented by Formula 1, including; preparing a compound represented by Formula 1 from the compound represented by Formula 4 prepared in Step 2 (step 3). :
  • R 4 and R 5 are each independently —H, halogen, unsubstituted or one or more halogen-substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, unsubstituted or substituted C 6-10 aryl, or R 4 and R 5 are linked to each other ego,
  • R 6 and R 7 are each independently —H, halogen, unsubstituted or substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, or R 6 and R 7 is a 3 to 15 membered cycloalkyl formed by connecting to each other,
  • the substituted C 6-10 aryl is C 1-5 straight or branched chain alkyl, C 1-5 straight or branched chain alkylcarbonyl, and at least one heteroatom selected from the group consisting of N, O and S C 6-10 aryl substituted with one or more substituents selected from the group consisting of 5 to 6 membered heteroaryl including;
  • Y is -H, halogen, -N 2 + , -NO 2 , -CN, straight-chain or branched C 1-5 alkoxy;
  • R 1 and R 2 are each independently —H, or t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2- an amine protecting group selected from the group consisting of trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc);
  • R 3 is hydrogen, a linear or branched C 1-10 alkyl , or a phenyl substituted with a straight or branched C 1-10 alkyl).
  • a precursor for synthesizing [ 18 F]FBPA having excellent yield and isomeric purity can be prepared using a tert-butyl group for R 3 .
  • the cycloalkyl may be a bridged cyclic, a fused cyclic, a spiro cyclic, or a branched cyclic.
  • R 4 and R 5 are each independently -H, halogen, unsubstituted or one or more halogen-substituted straight or branched C 1-10 alkyl , straight or branched C 1-3 alkoxy , unsubstituted or substituted C 6-8 aryl, or R 4 and R 5 are linked to each other ego,
  • R 6 and R 7 are each independently —H, halogen, unsubstituted or one or more halogen-substituted straight-chain or branched C 1-10 alkyl, straight - chain or branched C 1-3 alkoxy , or R 6 and R 7 is a cycloalkyl of 5 to 12 atoms formed by connecting to each other,
  • the substituted C 6-8 aryl is C 1-3 straight or branched chain alkyl, C 1-3 straight or branched chain alkylcarbonyl, and one or more heteroatoms selected from the group consisting of N, O and S one or more substituents selected from the group consisting of 5 to 6 membered heteroaryl including substituted C 6-8 aryl;
  • Y is -H, halogen, -N 2 + , or -NO 2 ;
  • R 3 may be hydrogen, straight - chain or branched C 1-10 alkyl.
  • X is ego
  • R 6 and R 7 are 8 to 11 membered cycloalkyl formed by connecting to each other
  • Y is halogen, or —N 2 + ;
  • the R 3 may be a straight - chain or branched C 3-6 alkyl.
  • X is ego
  • Y may be halogen
  • step 1 of Scheme I may be a nucleophilic substitution reaction with a [ 18 F]F anion.
  • step 2 of Scheme I may be performed using various Pd catalysts, preferably through Miyaura borylation, and most preferably Pd(dppf)Cl 2 ([1,1′-Bis (diphenylphosphino)ferrocene]dichloropalladium(II)).
  • Pd(dppf)Cl 2 [1,1′-Bis (diphenylphosphino)ferrocene]dichloropalladium(II)
  • step 3 of Scheme I may be performed under an acidic solution.
  • Another aspect of the present invention provides a compound represented by the following formula (2), a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof:
  • X is ego
  • R 6 and R 7 are 8 to 11 membered cycloalkyl formed by connecting to each other
  • Y may be halogen
  • said X is ego
  • Y may be halogen
  • X is ego
  • R 6 and R 7 are 8 to 11 membered cycloalkyl formed by connecting to each other
  • Y may be halogen
  • said X is ego
  • Y may be halogen
  • any solvent suitable for each experimental condition may be used without limitation, for example, an ether solvent including tetrahydrofuran (THF) dioxane ethyl ether, 1,2-dimethoxyethane, etc.
  • an ether solvent including tetrahydrofuran (THF) dioxane ethyl ether, 1,2-dimethoxyethane, etc.
  • lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonazensulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, ethyl acetate, phenylacetate, phenyl Propionate, Phenylbutyrate, Cycrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate, Naphthalene-2-sulfonate, Mandelate These may be used alone or in combination.
  • DMF dimethylformamide
  • DCM dichloromethane
  • dichloroethane water, acetonazensulfonate, toluene
  • the acetonitrile solution in which 5-bromo-2-methylaniline was dissolved was mixed with 30% sulfuric acid aqueous solution, and then the sodium nitrile aqueous solution was slowly added dropwise at 0 °C using a dropping funnel. After reacting the reaction solution at 0° C. for 1 hour, an aqueous sodium iodide solution was further added dropwise and reacted at room temperature for 1 hour. The final reaction solution was extracted three times using ethyl acetate, and the extracted organic solution was treated with brine and MgSO 4 to remove moisture, concentrated, and purified using column chromatography to purify the desired compound 4-bromo-2-io Do-1-methylbenzene ( A-1 ) was obtained in a yield of 60%.
  • N-bromosuccinimide and AIBN Azobisisobutyronitrile
  • acetonitrile solution in which Compound A-1 prepared in step 1 was dissolved, followed by reflux for 18 hours.
  • the reaction solution was passed through celite, the filtrate was concentrated and purified through column chromatography, and the desired compound 4-bromo-1-(bromomethyl)-2-iodobenzene ( A- 2 ) was obtained in a yield of 73%.
  • Step 3 Synthesis of tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-((diphenylmethylene)amino)propanoate (A-3)
  • N-diphenylmethylene glycine tert-butyl ester and Maruoka catalyst as an asymmetric phase transfer catalyst were added to a mixture of 45% KOH aqueous solution and toluene, and the reaction solution was lowered to 0 ° C., followed by vigorous stirring, Compound A prepared in step 2 -2 toluene solution was slowly added dropwise. The reaction was carried out at 0° C. for 18 hours, and after the reaction was completed, the organic layer extracted with diethyl ether three times was removed from moisture using brine and MgSO 4 , and then concentrated under reduced pressure.
  • Step 4 Synthesis of tert -butyl (S)-2-amino-3-(4-bromo-2-iodophenyl)propanoate (A-4)
  • Step 5 Synthesis of tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-(( tert -butoxycarbonyl)amino)-propanoate (A-5)
  • Step 6 Synthesis of tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-(( tert -butoxycarbonyl) 2 -amino)propanoate (A-6)
  • Boc 2 O and DMAP were added to the acetonitrile solution of Compound A-5 prepared in step 5, and reacted at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the desired compound tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-(( tert ) was subjected to column chromatography. -Butoxycarbonyl) 2 amino) propanoate ( A-6 ) was obtained in a yield of 98% and an ee value of 96% (FIG. 13).
  • Step 7 ( tert -butyl ( S )-3-(4-bromo-2-((4',6'-dioxospiro[tricyclo[5.3.1.1 3, 9 ]dodecane-10,2'-[1,3] Synthesis of dioxane]-5-'ylidene- ⁇ 3 -iodanyl)phenyl)-2-(( tert -butoxycarbonyl)amino)propanoate (A, precursor)
  • Acetic acid was added dropwise to the acetone solution of Compound A-6 prepared in step 6 on an ice bath and stirred for 1 hour, then DMDO prepared in step 7-2 was added dropwise to the reaction solution, the ice bath was removed, and the mixture was cooled to 3 time was stirred. After the reaction is complete, the solvent in the reaction solution is removed by concentration under reduced pressure, and the remaining reactant is added to (1r,3r,5r,7r)-spiro[adamantane-2,2'-[1,3]dioxane]- A solution of 4',6'-dione in 10% Na 2 CO 3 was added dropwise and reacted at room temperature for 2 hours.
  • the fluorine-18 anion required for the label synthesis of fluorine-18 was obtained by irradiating a 55uA proton beam to the isotope target (O-18 water) for 5 to 30 minutes using 11 MeV cyclotron (Siemens, USA). , an anion exchange resin column (QMA light Sep-Pak, Waters) was used to remove moisture and secure fluorine-18 anion. Cationic impurities that may remain in the anion exchange resin column were removed by using an appropriate amount of tertiary distilled water, and an organic solvent containing a phase transfer catalyst was flowed to extract the fluorine-18 anion from the column for use in synthesis.
  • an anion exchange resin column QMA light Sep-Pak, Waters
  • Fluorine-18 anion in the anion exchange resin column was placed in a reaction vessel (7ml borosilicate tube) by flowing tetraethylammoium bicarbonate solution (2.1 mg in MeOH 700 ul, D.W. 300 ul), and argon gas was heated while heating the reaction vessel to 110 ° C. Water and acetonitrile were evaporated by running. In order to sufficiently remove moisture, an additional 300 ul of acetonitrile was added and evaporated to dryness, and the same process was repeated 1-2 times to completely remove the remaining moisture.
  • the precursor ( A ) was dissolved in dimethylformamide (300 ul) in a reaction vessel, put into a reaction vessel, and reacted by heating at 120° C. for 10 minutes to synthesize B-1.
  • a small amount of the reaction solution was added dropwise to silica TLC, developed with n-Hex/EtOAc (10:1) developing solvent, and radiated using a radioactive TLC scanner (AR-2000, Apanpack). By measuring the chemical purity, it was confirmed that the Rf value of B-1 produced without side reaction was 0.47, and the synthesis yield was 60-70%.
  • step 3 To purify [ 18 F]FBPA, the result of step 3, add 1.3 ml of 0.1% TFA aqueous solution to the reaction solution and dilute it, then inject it into HPLC and use 5% acetonitrile aqueous solution (0.1% TFA water) at 4ml/min.
  • [ 18 F]FBPA separated and eluted by flowing at a flow rate was collected. The elution time was between 9 and 11 minutes, the UV wavelength was 254 nm, and a gamma ray detector installed in parallel with the UV was used for detection of radioactive compounds.
  • the purified [ 18 F]FBPA aliquot was diluted in 30 ml of tertiary distilled water and flowed through a reversed-phase column cartridge (C-18 Sep-Pak, waters) to remove the solvent, and the remaining 10 ml of tertiary distilled water was additionally flowed.
  • the solvent was sufficiently removed, and [ 18 F]FBPA was extracted by sequentially flowing 1 ml of ethanol and 9 ml of physiological saline, and the solution was passed through a sterile filter (Millex GV, Waters) and put into a sterile vial.
  • the radiochemical yield (non-attenuation correction) of the finally synthesized compound was about 10%, and when the synthesis was started with about 150 mCi of fluorine-18 anion, about 16 mCi of [ 18 F]FBPA could be obtained, The total synthesis time was about 2 hours.
  • [ 18 F]FBPA could be prepared with excellent yield and isomeric purity by using the precursor having a carboxyl group substituted with a t-butyl group prepared according to Example 1.
  • [ 18 F]FBPA the final product after synthesis and purification, was subjected to quality control such as radiochemical purity and specific activity.
  • the glass thin film used was a thin film plate with a size of 1 cm in width and 10 cm in length coated with silica gel, and at each stage, about 1 ul of the stock solution was dripped at the origin of the plate using a glass microtube without separate treatment of the reaction solution, and at each stage. Appropriate development conditions were used for development and analysis.
  • the fluorine-18 anion not participating in the first-step reaction remained as it is, and [ 18 F]FBPA, the final product of which hydrolysis occurred, was confirmed at an Rf value of 0.564.
  • the reaction mixture in the last step was separated and purified using HPLC, and analyzed by anal-HPLC to obtain final purity and component analysis (confirmation of FBPA components through co-injection).
  • FBPA standard material In order to identify the components of [ 18 F]FBPA obtained through fluorine-18 labeling synthesis, a non-radioactive material, FBPA standard material is required. FBPA can be obtained through organic synthesis, and the structure of the compound was identified through NMR analysis. The FBPA standard sample for checking the HPLC component analysis was synthesized as follows, and the overall reaction formula is shown in Scheme 3 below.
  • Step 1 Synthesis of test-butyl 3-(4-bromo-2-fluorophenyl)-2-((diphenylmethylene)amino)propanoate (C - 1)
  • Step 2 tert-Butyl 2-(bis(tert-butoxycarbonyl)amino)-3-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo Synthesis of lora-2-yl)phenyl)propanoate (C-2)
  • the automatic synthesizer was used to perform the synthesis of [ 18 F]FBPA with high radioactivity (over 100 mCi).
  • the automatic synthesis apparatus is an apparatus that performs synthesis according to the programmed sequence except for HPLC separation and purification, and here, Flexlab (iPhase, AUS), a general-purpose F-18 automatic synthesis apparatus, was used.
  • Flexlab iPhase, AUS
  • the reaction sequence is as follows.
  • Step 2 Reagent Preparation: Heat A at 100 °C 3 min and mix A to B
  • Vial 15 was loaded with 1 mL HPLC buffer.
  • HPLC was used to measure the radiochemical purity, and a small amount (20 ul) of the finally obtained compound was taken and injected into the HPLC.
  • the HPLC developing solvent was 5% acetonitrile (0.1% TFA aqueous solution), and it was flowed at a flow rate of 1 ml/min.
  • a UV detector was used to detect organic foreign substances, and a gamma ray detector (2x2” Nal) was used to detect radioactive organic substances. scintillation detector) was used alongside the UV detector.
  • the column used was a C18 column (4.6x250 mm, Agilent), with a UV detection wavelength of 254 nm and a gamma-ray detection energy band of 100-700 keV.
  • the radiochemical purity of [ 18 F]FBPA was 95% or more, and it was suitable for the standard value of radiochemical purity that is generally accepted in PET.
  • a standard sample (FBPA) was prepared at concentrations of 500, 250, 50, and 25 ppm, and each absorbance was measured in analytical HPLC to draw a quantitative line.
  • the UV absorbance for concentration can be calculated through the quantitative line, and the specific radioactivity of the synthesized [ 18 F]FBPA solution using an automatic synthesis device was found to have a value of at least 10 Ci/umol or more.
  • the FBPA peak between 6 and 8 minutes was below the detection limit, so it was confirmed that it had a very high specific radioactivity to the extent that analysis was impossible.

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Abstract

Est divulgué un procédé de production de 2-[18F]fluoro-4-boronophénylalanine comprenant des isotopes radioactifs ([18F]FBPA), le procédé comportant un précurseur présentant un groupe partant efficace et des conditions de réaction pour une synthèse à haut rendement de [18F]FBPA pour permettre au composé cible, [18F]FBPA, d'être efficacement synthétisé, et il peut être produit en masse à l'aide d'appareils de synthèse automatisés pour permettre une utilisation efficace dans des techniques d'imagerie moléculaire.
PCT/KR2020/017310 2020-11-30 2020-11-30 Procédé de production efficace de 2-[18f]fluoro-4-boronophénylalanine comprenant des isotopes radioactifs WO2022114333A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120123120A1 (en) * 2009-04-08 2012-05-17 The Regents Of The University Of California No-Carrier-Added Nucleophilic [F-18] Fluorination of Aromatic Compounds
JP2016204314A (ja) * 2015-04-23 2016-12-08 国立研究開発法人理化学研究所 化合物及び４−ボロノフェニルアラニン誘導体の製造方法
US9815855B2 (en) * 2014-02-28 2017-11-14 Stella Pharma Corporation Method for producing 4-borono-L-phenylalanine having 18F atom introduced thereinto, and precursor of 4-borono-L-phenylalanine having 18F atom introduced thereinto
CN109384806A (zh) * 2017-08-03 2019-02-26 王璐 一种[18f]fbpa新型制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120123120A1 (en) * 2009-04-08 2012-05-17 The Regents Of The University Of California No-Carrier-Added Nucleophilic [F-18] Fluorination of Aromatic Compounds
US9815855B2 (en) * 2014-02-28 2017-11-14 Stella Pharma Corporation Method for producing 4-borono-L-phenylalanine having 18F atom introduced thereinto, and precursor of 4-borono-L-phenylalanine having 18F atom introduced thereinto
JP2016204314A (ja) * 2015-04-23 2016-12-08 国立研究開発法人理化学研究所 化合物及び４−ボロノフェニルアラニン誘導体の製造方法
CN109384806A (zh) * 2017-08-03 2019-02-26 王璐 一种[18f]fbpa新型制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PETERSEN I. N., VILLADSEN J., HANSEN H. D., MADSEN J., JENSEN A. A., GILLINGS N., LEHEL S., HERTH M. M., KNUDSEN G. M., KRISTENSEN: "18 F-Labelling of electron rich iodonium ylides: application to the radiosynthesis of potential 5-HT 2A receptor PET ligands", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 15, no. 20, 1 January 2017 (2017-01-01), pages 4351 - 4358, XP055934325, ISSN: 1477-0520, DOI: 10.1039/C7OB00628D *

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