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WO2025114063A1 - Procédé stabilisé pour marquage au 18f - Google Patents

Procédé stabilisé pour marquage au 18f Download PDF

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Publication number
WO2025114063A1
WO2025114063A1 PCT/EP2024/082718 EP2024082718W WO2025114063A1 WO 2025114063 A1 WO2025114063 A1 WO 2025114063A1 EP 2024082718 W EP2024082718 W EP 2024082718W WO 2025114063 A1 WO2025114063 A1 WO 2025114063A1
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WO
WIPO (PCT)
Prior art keywords
radical scavenger
fdg
ppm
fluoride
concentration range
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Pending
Application number
PCT/EP2024/082718
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English (en)
Inventor
Gauthier Philippart
Jean-Luc Morelle
Corentin WARNIER
Laura TRUMP
Romaric GERARDY
Simon CERFONTAINE
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Trasis SA
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Trasis SA
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Priority claimed from BE20235959A external-priority patent/BE1031675B1/fr
Priority claimed from EP23212216.8A external-priority patent/EP4559890A1/fr
Application filed by Trasis SA filed Critical Trasis SA
Publication of WO2025114063A1 publication Critical patent/WO2025114063A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • C07B59/005—Sugars; Derivatives thereof; Nucleosides; Nucleotides; Nucleic acids
    • 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
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen

Definitions

  • the invention pertains to the field of chemical synthesis. More particularly, the invention pertains to methods for the synthesis of [18F]-labelled molecules, and more particularly to a method for stabilizing the radiolabelling outcome at high activity.
  • Positron Emission tomography (PET) and [ 18 F]-labeling Positron Emission Tomography (PET) imaging is a minimally invasive useful imaging technique that can produce three-dimensional images of processes in the body.
  • PET measures the physiological function by observing blood flow, metabolism, neurotransmitters and radiolabelled agents. This imaging technique is based on the indirect detection of gamma rays and radiation emitted by a radioactive agent that is injected into the body.
  • fluorine-18 (18F) is the most ideal due to its favorable decay scheme. The half-life of this radionuclide (110 min) allows time for multistep radiolabelling reaction and for delivery of 18 F- labelled tracers to distant user sites.
  • the short positron range (2.3 mm) in tissue and the ideal decay process (97% positron emission) contribute to offer high resolution images.
  • [18F]-fluoride is produced by irradiation of ‘enriched’ water, containing H2 18 O, with protons resulting in the reaction 18 O(p,n) 18 F. Only a minor fraction of the [ 18 O] is converted. The [ 18 F] isotope is then separated from the water and processed for production of a radiopharmaceutical agent.
  • fluoride recovery is based on the use of an anion-exchange resin.
  • the recovery is carried out in two steps, extraction and elution: first the anions (not only fluoride) are separated from the enriched [ 18 O] water and trapped on the said resin.
  • the anions, including [ 18 F]-fluoride are then eluted into a mixture containing water, organic solvents, a phase transfer agent or activating agent or phase transfer catalyst, such as for example the complex potassium carbonate-Kryptofix 222 (K2CO3-K222) or a tetrabutyl-ammonium salt.
  • the [ 18 F] fluoride radiochemical recovery yield is very effective, usually exceeding 99%.
  • nucleophilic substitution requires anhydrous or very low water content solutions.
  • an evaporation step or drying step
  • evaporation step is usually necessary after recovery to remove the excess water. It usually consists in multiple azeotropic evaporations of acetonitrile or of low boiling temperature organic solvent. Such evaporations require several minutes and these steps result in the creation of “naked”, highly nucleophilic [18F]- fluoride.
  • the subsequent [18F]-fluorination step can be classified as a nucleophilic aliphatic or aromatic substitution.
  • a prerequisite for [ 18 F]- substitutions is the presence of a good leaving group on the precursor to be labelled.
  • the halides Cl, Br and I or the different types of sulfonates – tosylates, nosylate, mesylate and triflate – are used most often in radiofluorination reactions.
  • the precursor dissolved in a polar aprotic solvent is added to the naked [ 18 F]-fluoride anions in the reactor and the nucleophilic substitution occurs.
  • the radiolabeling requires the reactor to be heated.
  • the nucleophilic substitution can be conducted on a solid-support cartridge, by loading the precursor solution on a cartridge which previously trapped the [ 18 F]-fluoride anions. The cartridge may be heated by a heating device to enhance the nucleophilic substitution reaction.
  • the radiolabeling step e.g. the nucleophilic substitution
  • the radiotracer synthesis outcome is crucial for the radiotracer synthesis outcome.
  • nucleophilic fluorination reaction is carried out in a polar aprotic solvent, such as acetonitrile (ACN), N,N-dimethylformamide (DMF), or dimethyl sulfoxide (DMSO), to increase the solubility of fluorine salt and the reactivity of fluoride.
  • ACN acetonitrile
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • polar aprotic solvents such as the aforementioned ACN, DMF and DMSO have been widely used as a solvent for these [ 18 F]-radiolabeling reactions.
  • the nucleophilicity of [18F]fluoride in polar aprotic solvents usually is enhanced through the selective solvation of its counter cations by the negative end of the polar aprotic solvent dipole and the lack of a proton for hydrogen bonding, which leave the [18F]- fluoride free or naked.
  • the tert-alcohol media such as tert-butyl alcohol and tert-amyl alcohol
  • tert-alcohol media greatly enhanced the reactivity of alkali metal fluorides.
  • the use of tert- alcohols could reduce the formation of typical byproducts (namely, alkenes, alcohols, or ethers) dramatically in the nucleophilic fluorination of base-sensitive compounds, such as 1-(2-mesylethyl)naphthalene and N-5-bromopentanoyl-3,4- dimethoxyaniline compared with the use of conventional polar aprotic solvents (Kim D.W., Ahn D.S., Oh Y.H., Lee S., Kil H.S., Oh S.J.
  • This TBAF(t-BuOH)4 also showed good performance in the nucleophilic fluorination because of its ideal favorable properties as a fluoride source, such as the dehydrated state for anhydrous reaction conditions, low hygroscopicity, good solubility in organic solvents, and good nucleophilicity with low basicity (Kim D.W., Jeong H.J., Lim S.T., Sohn M.H. Tetrabutylammonium tetra(tert-butyl alcohol)- coordinated fluoride as a facile fluoride source. Angew Chem Int Ed Engl (2008) 47:8404–8406).
  • the tert-alcohol must be present predominantly in the reaction media, e.g. as the solvent itself and not added as an adjuvant or a catalyst.
  • polar protic solvent such as primary or secondary alcohol, mainly because of their high intrinsic polarity.
  • Protecting groups are often necessary to eliminate acidic protons in the molecule that would diminish the nucleophilicity of [ 18 F]-fluoride. If protecting groups have been used, they must be removed after the radiolabeling step.
  • the product has to be purified by Solid Phase Extraction (SPE) or preparative High-Performance Liquid Chromatography (HPLC) and formulated for injection.
  • SPE Solid Phase Extraction
  • HPLC preparative High-Performance Liquid Chromatography
  • Radiolysis Because of the aforementioned short half-life of the [18F] isotope, [18F]-labelled radiotracers must be produced in relatively large activities to allow for decay during delivery to the patient from a manufacturing facility. It is well known that the major stability issue for radiopharmaceuticals is radiolysis which can be either auto-radiolysis, self-destruction by its own radiation, and/or attack by free radicals formed by the radiation on environmental species.
  • Radio-stabilizers There are several strategies to reduce radiolysis: one common and well documented strategy is to stabilize the final product with radio-stabilizers.
  • the most well-known and frequently used radio-stabilizer for [ 18 F]-FDG is ethanol.
  • Adding ethanol to the formulation of the final product in 0,1 – 0,4 % concentration has proven effective to stabilize [ 18 F]-FDG with activity up to 25 GBq/ml up to 16 hours (Dantas N.M., Nascimento J.E., Santos-Magalh ⁇ es N.S., Oliveira M.L., Radiolysis of2-[18F]fluoro-2 deoxy-D-glucose ([18F]FDG) and the role of ethanol, radioactive concentration and temperature of storage. Appl Radiat Isot.
  • the dilution factor for the product as a stabilizer must also be considered, but the dilution has limitations due to the maximum volume to be injected, and additionally a radio-stabilizer can be considered (Jiménez Romero I.R., Roca Engronyat M., Campos A ⁇ ón F., Cordero Ramajo J., Liarte Tr ⁇ as I., Ben ⁇ tez Segura A., Bajén Lázaro M., Ferrán Sureda N., Puchal A ⁇ é R., Gámez Cenzano C., Influence of radioactive concentration and storage time on radiochemical purity of 18F-FDG.
  • Radiotracers with high specific activity provide better sensitivity and accuracy in detecting the target biological process or molecule within the body.
  • higher incorporation allows for the synthesis of radiotracers with a lower mass of the cold (non-radioactive) component. This is important because even a small mass of the carrier molecule can interfere with the biological processes under investigation, potentially leading to biased images or unwanted side effects.
  • radiotracers with high specific activity provide sharper PET images.
  • the invention aims at stabilizing the radiochemical yields of radiochemical synthesis of [18F]-labeled radiotracers obtained through nucleophilic aliphatic or aromatic substitution whatever the level of starting radioactivity used.
  • the present invention relates to the stabilization toward radiolysis of radiosynthetic intermediates, including cold intermediates such as the precursor to be radiolabelled, by the use of radical scavengers during the nucleophilic [ 18 F]-fluorination step of a radiochemical synthesis of a [ 18 F]-labeled radiotracer.
  • the nucleophilic [ 18 F]-fluorination step can be classified as aliphatic or aromatic. The former is encountered in the [ 18 F]-FDG synthesis.
  • [ 18 F]-FDG The usual synthesis of [ 18 F]-FDG is a two-step process consisting of two chemical reactions: a nucleophilic [ 18 F]- fluorination of a mannose triflate precursor (1,3,4,6-tetra-O-acetyl-2-O- trifluoromethanesulfonyl- ⁇ -D-mannopyranose) followed by a hydrolysis step of some protecting groups.
  • the substitution reaction is accomplished in polar aprotic solvents, such as acetonitrile, after a few drying steps. At high activity, the substitution reaction can lead to numerous by-products, due to radiolysis, negatively impacting the production yield (examples 1-12).
  • the invention aims to stabilizing the [18F]-labeled radiotracer production outcome by stabilizing the labeling yield whatever the starting activity, through the addition of a radical scavenger in the reaction vessel.
  • Manufacturing of a [18F]-labelled molecule through a nucleophilic [18F]-fluorination step begins with the production of [18F]fluoride in a cyclotron.
  • Two important characteristics of cyclotrons pertaining to the production of [18F]- fluoride are the proton beam energy and the beam current being used. These two factors, along with the target volume, will determine how much [ 18 F]-fluoride quantity, i.e. the activity, can be produced in a given amount of time.
  • the expression “high activity” for a solution will refer to solutions with activity higher than 37 GBq, preferably more than 100 GBq and more preferably more than 500 GBq.
  • the radical scavenger species could be a polar protic compound, if added in specific concentrations (examples 13-31).
  • the radical scavenger is an alcohol.
  • the radical scavenger is a primary or secondary alcohol, more preferably a primary alkanol, still more preferably methanol or ethanol with still a preference for ethanol.
  • said [18F]-labelled radiotracer are selected from, but not limited to, [18F]-NaF, [18F]-FDG, [18F]-FMISO, [18F]-FLT, [ 18 F]-FAZA, [ 18 F]-FCH, [ 18 F]-FDOPA, [ 18 F]-FES, [ 18 F]-FET, [ 18 F]-FAPI derivatives.
  • the radical scavenger concentration range is from 5000 ppm to 30000 ppm. [0025] In some other preferred embodiments, the radical scavenger concentration range is from 10000 ppm to 25000 ppm. [0026] In some other preferred embodiments, the radical scavenger concentration range is from 5000 to 15000 ppm. [0027] In some other preferred embodiments, the radical scavenger concentration range is from 15000 to 25000 ppm. [0028] In some other preferred embodiments, the radical scavenger concentration range is from 15000 to 20000 ppm. [0029] In some other preferred embodiments, the radical scavenger concentration range is from 15000 to 28000 ppm.
  • the [18F]-labelled radiotracer is [ 18 F]-FDG at high activity
  • the radical scavenger is ethanol in a concentration range of the from 10000 to 20000 ppm, the stabilized non-decay corrected yield being higher than 65%.
  • the [18F]-labelled radiotracer is [ 18 F]-FDG
  • the radical scavenger is ethanol
  • the concentration range of the radical scavenger is from 5000 to 20000 ppm.
  • the synthesis of [18F]-labelled molecules using the method according to the present disclosure may be carried out manually, or using an automated radiosynthesizer.
  • cassette means an equipment unit constructed so that the entire unit fits removably and interchangeably on an automatic synthesizer device (as defined above) in such a way that the mechanical movement of moving parts of the synthesizer controls the operation of the cassette from outside the cassette.
  • Suitable cassettes consist of a linear array of valves, each connected to a port to which reagents or vials can be connected, either by needle insertion into a vial sealed with an inverted septum or by gas- tight connectors.
  • the cassette is versatile as it usually has several positions where reagents can be attached, as well as several positions suitable for attaching syringes or chromatography cartridges (e.g. for solid phase extraction or SPE).
  • the cassette always includes at least one reaction vessel.
  • This invention is not dependent on the details of the above examples and should apply to any process that uses a nucleophilic [18F]- fluorination step.
  • EXAMPLES Examples 1-12 synthesis of [ 18 F]-FDG at high activity without the presence of a radical scavenger during the labeling step.
  • the automated synthesis of [18F]-FDG was performed on the AllinOne® synthesizer (Trasis SA, Belgium). Briefly, [ 18 F]-fluoride obtained from the bombardment of enriched [ 18 O]-water was trapped on a carbonated QMA Plus light cartridge (130 mg of sorbent, the QMA was used as received).
  • Examples 13-24 Synthesis of -FDG in the presence of ethanol during the labeling step at low General procedure
  • Illustrative examples of the present invention is the automated synthesis of [ 18 F]-FDG on the AllinOne® synthesizer (Trasis SA, Belgium). Briefly, [ 18 F]-fluoride obtained from the bombardment of enriched [ 18 O]-water was trapped on a carbonated QMA Plus light cartridge (46 mg of sorbent, the QMA was used as received). An aliquot of the K2CO3/K222 containing eluent (300 ⁇ L) was used to elute the trapped [18F]-fluoride to the reaction vessel.
  • NDC Non-Decay Corrected
  • Examples 25-31 Synthesis of [18F]-FDG in the presence of ethanol during the labeling step at high activity
  • the automated synthesis of [18F]-FDG was performed on the AllinOne® synthesizer (Trasis SA, Belgium). Briefly, [ 18 F]-fluoride obtained from the bombardment of enriched [ 18 O]-water was trapped on a carbonated QMA Plus light cartridge (46 mg of sorbent, the QMA was used as received). An aliquot of the K2CO3/K222 containing eluent (300 ⁇ L) was used to elute the trapped [18F]- fluoride to the reaction vessel.
  • NDC Non-Decay Corrected
  • [ 18 F]-fluoride obtained from the bombardment of enriched [ 18 O]-water was trapped on a carbonated QMA Plus light cartridge (46 mg of sorbent, the QMA was used as received).
  • An aliquot of the K 2 CO 3 /K222 containing eluent (300 ⁇ L) was used to elute the trapped [ 18 F]- fluoride to the reaction vessel.
  • an aliquot of the precursor dissolved in ethanol was added to the reactor and the labelling was carried out at 115 °C during 1.5 min.

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  • Chemical & Material Sciences (AREA)
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Abstract

La présente invention concerne un procédé de stabilisation du rendement de production de radiotraceurs marqués [18F] par ajout d'un piégeur de radicaux dans les milieux réactionnels de l'étape de fluoration [18F] nucléophile.
PCT/EP2024/082718 2023-11-27 2024-11-18 Procédé stabilisé pour marquage au 18f Pending WO2025114063A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
BEBE2023/5959 2023-11-27
BE20235959A BE1031675B1 (fr) 2023-11-27 2023-11-27 Methode stabilisée pour le marquage au 18f
EP23212216.8A EP4559890A1 (fr) 2023-11-27 2023-11-27 Procédé stabilisé pour l'étiquetage 18f
EP23212216.8 2023-11-27

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WO2025114063A1 true WO2025114063A1 (fr) 2025-06-05

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7018614B2 (en) 2002-11-05 2006-03-28 Eastern Isotopes, Inc. Stabilization of radiopharmaceuticals labeled with 18-F
WO2006065038A1 (fr) 2004-12-15 2006-06-22 Futurechem Co., Ltd. Procede pour la preparation de composes organofluores dans des solvants alcooliques
US9895454B2 (en) * 2014-07-03 2018-02-20 The Regents Of The University Of California Metal oxide catalyzed radiofluorination
US20210047327A1 (en) * 2018-01-24 2021-02-18 Ac Immune Sa Diagnostic compositions for pet imaging, a method for manufacturing the diagnostic composition and its use in diagnostics

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7018614B2 (en) 2002-11-05 2006-03-28 Eastern Isotopes, Inc. Stabilization of radiopharmaceuticals labeled with 18-F
WO2006065038A1 (fr) 2004-12-15 2006-06-22 Futurechem Co., Ltd. Procede pour la preparation de composes organofluores dans des solvants alcooliques
US9895454B2 (en) * 2014-07-03 2018-02-20 The Regents Of The University Of California Metal oxide catalyzed radiofluorination
US20210047327A1 (en) * 2018-01-24 2021-02-18 Ac Immune Sa Diagnostic compositions for pet imaging, a method for manufacturing the diagnostic composition and its use in diagnostics

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
BURIOVA EMACASEK FKROPACEK M.PROCHAZKA L.AUTORADIOLYSIS OF 2-DEOXY-2-[18F]FLUORO-D-GLUCOSERADIOPHARMACEUTICAL., J RADIOANAL NUCL CHEM., vol. 3, 2005, pages 595 - 602
DANTAS N.M.NASCIMENTO J.E.SANTOS-MAGALHAES N.SOLIVEIRA M.L: "Radiolysis of2-[18F]fluoro-2 deoxy-D-glucose ([18F]FDG) and the role of ethanol, radioactive concentration and temperature of storage.", APPL RADIAT ISOT., vol. 72, 2013, pages 158 - 62
DONG WOOK KIM ET AL: "A New Class of SN2 Reactions Catalyzed by Protic Solvents: Facile Fluorination for Isotopic Labeling of Diagnostic Molecules", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 128, no. 50, 1 January 2006 (2006-01-01), pages 16394 - 16397, XP055033268, ISSN: 0002-7863, DOI: 10.1021/ja0646895 *
FAWDRY R.M.: "Radiolysis of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and the role of reductant stabilisers.", APPL RADIAT ISOT., vol. 65, 2007, pages 1193 - 201, XP022302097, DOI: 10.1016/j.apradiso.2007.05.011
HJELSTUEN O.KSVADBERG AOLBERG D.EROSSER M: "Standardization of fluorine-18 manufacturing processes: new scientific challenges for PET", EUR J PHARM BIOPHARM., vol. 78, 2011, pages 307 - 13, XP028241944, DOI: 10.1016/j.ejpb.2011.01.002
HOLLER J.GRENMAELMO B.FJELLAKSEL R.: "Stability evaluation of [18F]FDG: literature study, stability studies from two different PET centres and future recommendations", EJNMMI RADIOPHARMACY AND CHEMISTRY, vol. 7, 2022, pages 2 - 20
JACOBSON M.SDANKWART H.R.MAHONEY D.W: "Radiolysis of 2-[18F]fluoro-2-deoxy-D-glucose([18F]FDG) and the role of ethanol and radioactive concentration", APPL RADIAT ISOT., vol. 67, 2009, pages 990 - 5, XP026037492, DOI: 10.1016/j.apradiso.2009.01.005
JIMÉNEZ ROMERO I.R.ROCA ENGRONYAT M.CAMPOS ANON F.CORDERO RAMAJO J.LIARTE TRÍAS IBENÍTEZ SEGURA A.BAJÉN LAZARO M.FERRAN SUREDA N.P: "Influence of radioactive concentration and storage time on radiochemical purity of 18F-FDG", REV ESP MED NUCL., vol. 45, 2006, pages 20 - 5
JÓSZAI ISVIDRÓ M.PÓTÁRI N.: "Recommendations for selection of additives for stabilization of [18F]FDG", APPL RADIAT ISOT., vol. 146, 2019, pages 78 - 83
JÓSZAI ISVIDRÓ M.POTARI N.: "Recommendations for selection of additives for stabilization of [18F]FOG.", APPL RADIAT ISOT., vol. 146, 2019, pages 78 - 83
KIM D.W.JEONG H.J.LIM S.TSOHN M.H: "Recent Trends in the Nucleophilic [18F]-radiolabeling Method with No-carrier-added [18F]fluoride.", NUCL MED MOL IMAGING, vol. 44, 2010, pages 25 - 32
KIM D.W.JEONG H.JLIM S.T.SOHN M.H.KATZENELLENBOGEN J.A.CHI D.Y.: "Facile nucleophilic fluorination reaction using tert-alcohols as a reaction medium: significantly enhanced reactivity of alkali metal fluorides and improved selectivity.", J ORG CHEM, vol. 73, 2008, pages 957 - 962
KIM D.WAHN D.SOH Y.H.LEE SKIL H.SOH S.J: "A new class of SN2 reactions catalyzed by protic solvents: facile fluorination for isotopic labeling of diagnostic molecules", J AM CHEM SOC, vol. 128, 2006, pages 16393 - 16397
KIM D.WAHN D.SOH Y.HLEE SKIL H.S.OH S.J.: "A new class of SN2 reactions catalyzed by protic solvents: facile fluorination for isotopic labeling of diagnostic molecules.", J AM CHEM SOC, vol. 128, 2006, pages 16393 - 16397
KIM D.WJEONG H.J.LIM S.T., SOHN M.H: "Tetrabutylammonium tetra(tert-butyl alcohol)-coordinated fluoride as a facile fluoride source.", ANGEW CHEM INT ED ENGL, vol. 47, 2008, pages 8404 - 8406
KIM D.WJEONG H.JLIM S.T.SOHN M.HCHI D.Y: "Facile nucleophilic fluorination by synergistic effect between polymersupported ionic liquid catalyst and tert-alcohol", TETRAHEDRON, vol. 64, 2008, pages 4209 - 4214, XP022589405, DOI: 10.1016/j.tet.2008.02.094
KIM DONG WOOK ET AL: "Supplementary Information: A New Class of SN2 Reactions Catalyzed by Protic Solvents: Facile Fluorination for Isotopic Labeling of Diagnostic Molecules", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1 January 2006 (2006-01-01), pages S1 - S3, XP093173836, Retrieved from the Internet <URL:https://ndownloader.figstatic.com/files/4743982> *
MOSDZIANOWSKI C.LEMAIRE C.SIMOENS FAERTS J.MORELLE J.-LLUXEN A: "Epimerization study on [18F]FDG produced by an alkaline hydrolysis on solid support under stringent conditions", APPL RADIAT ISOT., vol. 56, 2002, pages 871 - 5, XP004354539, DOI: 10.1016/S0969-8043(01)00145-2
ORIT JACOBSON ET AL: "Fluorine-18 Radiochemistry, Labeling Strategies and Synthetic Routes", BIOCONJUGATE CHEMISTRY, vol. 26, no. 1, 4 December 2014 (2014-12-04), US, pages 1 - 18, XP055387727, ISSN: 1043-1802, DOI: 10.1021/bc500475e *
WALTERS L.RMARTIN K.JACOBSON M.S.HUNG J.C.MOSMAN E.A.: "Stability evaluation of 18F-FDG at high radioactive concentrations", J NUCL MED., vol. 2413, 2011

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