BE1031675B1 - STABILIZED METHOD FOR 18F MARKING - Google Patents

Abstract

The present invention relates to a method for stabilizing the production yield of [18F]-labeled radiotracers by adding a radical scavenger to the reaction medium of the [18F] nucleophilic fluorination step.

Description

STABILIZED METHOD FOR 18F MARKING

Field of invention

[0001] The invention relates to the field of chemical synthesis. More particularly, the invention relates to methods for synthesizing molecules labeled with [°F], and more particularly to a method for stabilizing the result of high activity radiolabeling.

Background and Prior Art

Positron emission tomography (PET) and ['$F] labeling

[0002] Positron emission tomography (PET) imaging is a useful, minimally invasive imaging technique that can produce three-dimensional images of body processes. PET measures physiological function by observing blood flow, metabolism, neurotransmitters, and radiolabeled agents. This imaging technique relies on the indirect detection of gamma rays and radiation emitted by a radioactive agent injected into the body.

[0003] Among all the positron emitters available for PET, fluorine-18 (18F) is the most ideal due to its favorable decay pattern. The half-life of this radionuclide (110 min) allows a multi-step radiolabeling reaction and the delivery of 1?F-labeled tracers to remote user sites. In addition, the short positron range (2.3 mm) in tissues and the ideal decay process (97% positron emission) contribute to providing high-resolution images. As a result, the vast majority of PET tracers used clinically are 13F-labeled molecules, such as ['3F] isotope-labeled glucose, [18F]2-Fluoro-2-Deoxy-D-glucose (hereinafter [13F]-FDG), which is widely used worldwide in nuclear medicine for diagnostic studies using the technique of

Body PET scan.

[0004] ["°F]-fluoride is produced by irradiation of "enriched" water, containing

H2"80, with protons leading to the reaction "°O(p,n)"8F. Only a minor fraction of the ['®O] is converted. The isotope ['3F] is then separated from the water and processed for the production of a radiopharmaceutical agent.

[0005] In current practice, 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 [130]-enriched water and trapped on said resin. The anions, including [‘*F]-fluoride, are then eluted in a mixture containing water, organic solvents, a phase transfer agent or phase transfer activator or catalyst, such as potassium carbonate-Kryptofix 222 (K2CO3-K222) complex or a tetrabutylammonium salt. The radiochemical recovery yield of [°F] fluoride is very efficient, generally exceeding 99%.

[0006] The most common labeling method, known as nucleophilic substitution, requires anhydrous or very low water content solutions.

Thus, an evaporation step (or drying step) is usually necessary after recovery to remove excess water. || This usually involves multiple azeotropic evaporations of acetonitrile or low-boiling organic solvent. Such evaporations take several minutes and result in the creation of highly nucleophilic, "naked" [13F] fluoride.

[0007] The following [13F] fluorination step can be classified as an aliphatic or aromatic nucleophilic substitution. A prerequisite for [13F] substitutions is the presence of a good leaving group on the precursor to be labeled. In this regard, the halides Cl, Br and | or the different types of sulfonates — tosylates, nosylate, …— mesylate and triflate — are most often used in radiofluorination reactions.

After evaporation, the precursor dissolved in a polar aprotic solvent is added to the bare [‘*F]-fluoride anions in the reactor and nucleophilic substitution occurs.

Usually, radiolabeling requires the reactor to be heated.

Alternatively, nucleophilic substitution can be performed on a solid-support cartridge, by loading the precursor solution onto a cartridge that has previously trapped the fluoride anions [13F]. The cartridge can be heated by a heater to enhance the nucleophilic substitution reaction. In any case, the outcome of the radiolabeling step, e.g. the nucleophilic substitution, is crucial for the outcome of the radiotracer synthesis.

[0008] Generally, the 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 the fluorine salt and the reactivity of the fluoride. It is known that protic solvents, such as water or alcohol, are not suitable for the nucleophilic fluorination reaction, because protic solvents reduce the nucleophilicity of fluoride ['3F] by extensive hydrogen bonding and interaction with the partial positive charge of these solvents. Therefore, polar aprotic solvents, such as the above-mentioned ACN, DMF and DMSO, have been widely used as the solvent for these ['?F] radiolabeling reactions. The nucleophilicity of [13F]-fluoride in polar aprotic solvents is generally enhanced by the selective solvation of its countercations by the negative end of the polar aprotic solvent dipole and the lack of a proton for hydrogen bonding, leaving the [13F]-fluoride free or bare. However, in an effort to optimize labeling yields, a highly efficient aliphatic nucleophilic fluorination and ['?F]-radiofluorination method with alkali metal fluorides or [13F]-fluoride using nonpolar protic tertiary alcohols as the reaction solvent has been reported (Kim D.W., Ahn D.S., Oh Y.H., Lee S., Kil 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 (2006) 128: 16393-16397; patent application

WO 2006/065038A1). In this method, tertiary alcohol media, such as tert-butyl alcohol and tert-amyl alcohol, significantly improve the reactivity of alkali metal fluorides. In particular, the use of tertiary alcohols could significantly reduce the formation of typical by-products (i.e., alkenes, alcohols or ethers) in the nucleophilic fluorination of base-sensitive compounds, such as 1-(2-mesylethyl)naphthalene and N-5-bromopentanoyl-3,4-dimethoxyaniline compared to the use of conventional polar aprotic solvents (Kim D.W., Ahn

D.S., Oh Y.H., Lee S., Kil 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 (2006) 128: 16393-16397; Kim D.W, Jeong HJ. Lim S.T, Sohn MH,

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 (2008) 73: 957-962; Kim D.W., Jeong H.J., Lim

S.T., Sohn M.H., Chi D.Y., Facile nucleophilic fluorination by synergistic effect between polymersupported ionic liquid catalyst and tert-alcohol, Tetrahedron (2008) 64: 4209-4214). On the contrary, the results show that the use of primary or secondary alcohols, which are polar protic solvents, such as ethanol, lead to the production of by-products due to their polar character, thus significantly lowering the labeling yield.

[0009] Because this finding contrasted sharply with expectations from the conventional [‘“F]-radiofluorination route, the reaction mechanism of nucleophilic fluorination in a nonpolar protic tertiary alcohol solvent was reported (Kim

D.W., Jeong H.J. Lim S.T., Sohn M.H., Recent Trends in the Nucleophilic [!*F]- radiolabeling Method with No-carrier-added ["*F] fluoride, Nucl Med Mol Imaging (2010) 44:25-32). The authors suggested the mechanism: limited solvation of [13F]- fluoride coordinated with bulky tertiary alcohols (so-called "flexible" fluoride) could make fluoride a particularly efficient nucleophile in this medium; the reactivity of the leaving group could be enhanced by hydrogen bonding between the tertiary alcohol solvent and oxygen atoms of a sulfonate leaving group; side reactions, such as intramolecular eliminations, hydroxylations, and alkylations, could be suppressed by the protic environment, especially when using base-sensitive precursors (Kim D.W., Jeong H.J.,

Lim 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 (2008) 73:957—962; Kim

D.W., Jeong H.J., Lim S.T., Sohn M.H., Chi D.Y., Facile nucleophilic fluorination by — synergistic effect between polymersupported ionic liquid catalyst and tert-alcohol,

Tetrahedron (2008) 64:42094214). In a more recent paper, it was proven that “flexible” fluoride could be formed during the fluorination treatment of tertiary alcohol media following the preparation of tetrabutylammonium tetra t-butanol coordinated fluoride, TBAF(t-BUOH)4, from TBAF in commercially available t-BuOH. This TBAF(t-BuOH)4 also showed good performance in nucleophilic fluorination due to its ideal favorable properties as a fluoride source, such as 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). To obtain such a “flexible” fluoride, the tertiary alcohol must be mainly present in the reaction media, e.g. as a solvent itself and not added as an adjuvant or catalyst. Obviously, such a “flexible” fluoride is not accessible with the use of polar protic solvents such as primary or secondary alcohol, mainly due to their high intrinsic polarity.

[0010] Protecting groups are often necessary to remove acidic protons in the molecule that would decrease the nucleophilicity of the [13F]-fluoride. If protecting groups have been used, they must be removed after the radiolabeling step. Finally, the product must be purified by solid phase extraction (SPE) or preparative high performance liquid chromatography (HPLC) and formulated for injection.

Radiolysis

[0011] Due to the aforementioned short half-life of the [1?F] isotope, ['3F]-labeled radiotracers must be produced in relatively high activities to predict decomposition during delivery to the patient from a production site. It is well known that the major stability problem of radiopharmaceuticals is radiolysis which can be either autoradiolysis, i.e. self-destruction by its own radiation, and/or attack by free radicals formed by radiation on environmental species. Radiolysis, or more specifically autoradiolysis, of ['3F]-FDG has been widely studied and mainly yields free [‘F]-fluoride ions (Jôszai |, Svidré M., Pótári N,

Recommendations for selection of additives for stabilization of ["°F]-FDG; Appl Radiat

Isot. (2019) 146:78–83) and free radicals due to the reaction of ionizing radiation with water (Buriova E., Macasek F., Kropacek M., Prochazka L., Autoradiolysis of 2-deoxy-2-[*F]fluoro-D-glucoseradiopharmaceutical; J Radioanal Nucl Chem. (2005) 3:595–602).

[0012] There are several strategies to reduce radiolysis: a common and well-documented strategy is to stabilize the final product with radiostabilizers. The best known and most frequently used radiostabilizer for [18F]-FDG is — ethanol. The addition of ethanol to the final product formulation at a concentration of 0.1 to 0.4% has been shown to be effective in stabilizing [13F]-FDG with an activity of up to 25

GBq/mI for 16 hours (Dantas N.M., Nascimento J.E., Santos-Magalhäes N.S.,

Oliveira M.L., Radiolysis of 2-['3FJ]fluoro-2 deoxy-D-glucose ([18F]FDG) and the role of ethanol, radioactive concentration and temperature of storage; Appl Radiat Isot. (2013) 72:158-862; Fawdry R.M., Radiolysis of 2-['3F]fluoro-2-deoxy-D-glucose (FDG) and the role of reductant stabilizers; Appl Radiat Isot. (2007) 65:1193-201; Jacobson M.S.,

Dankwart HR, Mahoney D.W, Radiolysis of = 2-['*F]fluoro-2-deoxy-D-glucose([18F]FDG) and the role of ethanol and radioactive concentration; Appl Radiat

Isot. (2009) 67:990-5; Walters L.R., Martin K.J., Jacobson M.S., Hung J.C., Mosman

E.A, Stability evaluation of '8F-FDG at high radioactive concentrations. J Nucl Med.

(2011) 52(supplement 1):2413; patent application US7018614B2; Mosdzianowski C.,

Lemaire C., Simoens F., Aerts J., Morelle J.-L., Luxen A., Epimerization study on [‘8F]-

FDG produced by an alkaline hydrolysis on solid support under stringent conditions;

Radiat Isot app. (2002) 56:871-5; Jószai |, Svidré M., Pótári N, … Recommendations for selection of additives for stabilization of [*F]FDG. Application

Radiat Isot. (2019) 146:78-83; Holler J.G., Renmælmo B., Fjellaksel R., Stability evaluation of ["*F]FDG: literature study, stability studies from two different PET and future recommendations. EJNMMI Radiopharmacy and Chemistry (2022) 7:2-20).

[0013] The dilution factor of the product as a stabilizer must also be taken into account, but the dilution has limits due to the maximum volume to be injected, and in addition a radio-stabilizer can be considered (Jiménez Romero |.R., Roca Engronyat M.,

Campos Añôn F., Cordero Ramajo J., Liarte Trias |., Benítez Segura A., Bajén Lázaro

M., Ferrán Sureda N., Puchal Añé R., Gâmez Cenzano C., Influence of radioactive concentration and storage time of radiochemical purity of "“F-FDG. Rev Esp Med Nucl. (2006) 45:20-5; Hjelstuen O.K., Svadberg A., Olberg D.E., Rosser M., Standardization of fluorine -18 manufacturing processes: new scientific challenges for PET Eur. J Pharm

Biopharm. (2011) 78: 307-13.

WO 2006/065038 A1 discloses a method for preparing organofluorine compounds containing the radioactive isotope fluorine-18. More particularly, this document relates to a method for preparing an organofluorine compound by reacting a fluorine salt containing a radioactive isotope fluorine-18 with an alkyl halide or an alkyl sulfonate in the presence of an alcohol as a solvent to obtain a high yield of the organofluorine compound. The synthesis reaction according to this invention can be carried out under mild conditions to give a high yield of the organofluorine compounds and the reaction time is reduced, and the reaction is thus suitable for mass production of the organofluorine compounds.

Problem to solve

[0014] Although the above-mentioned prior art studies only provide solutions for improving the stability of the radiolabeled final product, it is interesting to address radiolysis upstream, mainly during the labeling step. It is essential to maximize the incorporation of [13F]-fluoride during the radiolabeling step to significantly increase the production yield, the number of injectable doses per production, and consequently to reduce the cost of the doses to be administered.

[0015] Furthermore, since PET imaging relies on the detection of positrons emitted by the decay of [1?F]-labeled radiotracers, higher incorporation of ['3F] into the precursor molecule results in higher specific activity of the radiotracer. Radiotracers with high specific activity provide better sensitivity and accuracy in detecting the biological process or target molecule in the body. Furthermore, higher incorporation allows for the synthesis of radiotracers with a lower mass of cold (non-radioactive) component. This is important because even a small mass of the carrier molecule can interfere with the biological processes being studied, potentially leading to biased images or undesirable side effects. Finally, radiotracers with high specific activity provide sharper PET images. This improved resolution allows for better localization and quantification of the biological target, thereby contributing to accurate diagnosis and treatment monitoring.

[0016] Maximizing the incorporation of [13F] into a precursor molecule is therefore crucial to produce high quality radiotracers with optimal imaging sensitivity, accuracy and resolution, but also for a more effective patient outcome as it will lead to improved radiotracer production results. However, achieving high incorporation rates, especially at high activity levels, is challenging due to the increased likelihood of radiolysis (where high energy radiation breaks chemical bonds in the precursor molecule), the complexity of the reaction and shorter reaction times.

Overcoming these challenges requires careful optimization of reaction conditions.

Aims of the invention

[0017] The present invention aims to avoid decomposition reactions, i.e. radiolysis resulting from high concentrations of radioactivity, of radiosynthetic intermediates used in the synthesis of [13F]-labeled radiotracers by the use of radical scavengers during the [1?F] nucleophilic fluorination step. In other words, the invention aims to stabilize the radiochemical yields of [13F]-labeled radiotracers obtained by aliphatic or aromatic nucleophilic substitution regardless of the starting level of radioactivity used.

Disclosure of the invention

[0018] The present invention relates to the stabilization for radiolysis of radiosynthetic intermediates, including cold intermediates such as the precursor to be radiolabeled, by the use of radical scavengers during the [13F] nucleophilic fluorination step of a radiochemical synthesis of a ["°F]-labeled radiotracer.

[0019] Depending on the precursor to be labeled, the [18F] nucleophilic fluorination step can be classified as aliphatic or aromatic. The former is encountered in the synthesis of [13F]-FDG. The usual synthesis of [13F]-FDG is a two-step process consisting of two chemical reactions: a [1?F]- nucleophilic fluorination of a mannose triflate precursor (1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-B-D-mannopyranose) followed by a hydrolysis step of some protecting groups. The substitution reaction is carried out in polar aprotic solvents, such as acetonitrile, after some drying steps. At high activity, the substitution reaction can lead to numerous by-products, due to radiolysis, negatively impacting the production yield (Examples 1 to 12). The invention aims to stabilize the production result of radiotracers labeled with [SF] by stabilizing the labeling yield regardless of the initial activity, thanks to the addition of a radical scavenger in the reaction vessel.

[0020] The manufacture of a ['3F]-labeled molecule by a [13F]-nucleophilic fluorination step begins with the production of [13F] fluoride in a cyclotron.

Two important characteristics of cyclotrons related to ["°F]-fluoride production are the proton beam energy and the beam current used. These two factors, together with the target volume, will determine the amount of [1?F]-fluoride, i.e. the activity, that can be produced in a given time period. To some extent, the higher the beam energy and current, the greater the fluoride production. All currently commercially available cyclotrons are capable of generating a beam with a current of at least 50 HA. Liquid targets used for [13F] production generally do not exceed 100 HA due to the limitation imposed by the dissipation of heat generated during irradiation.

Typically, a given target with a given operating pressure has an optimum current, at which the production rate is highest. It does not have to be the highest possible current. Most of today's powerful and efficient cyclotrons can produce up to 1480 GBq of [13F] fluoride. Since radiolysis can already occur at activities as low as -3.5 GBq, it is crucial to find solutions against radiolysis at such activity levels to stabilize the labeling yield and thus the output of [13F]-labeled radiotracers regardless of the starting activity.

[0021] In an effort to stabilize the above-mentioned yields, the inventors surprisingly discovered that the type of radical scavenger can be ethanol, if added at specific concentrations, i.e., 5000 to 20000 ppm (Examples 13 to 22 and 25-27).

[0023] In some embodiments, said [13F]-labeled radiotracers are selected from, but are not limited to, [13F]-NaF, [18F]-FDG, [$F]-NaF derivatives.

FMISO, [13F]-FLT, ['$F]-FAZA, [$F]-FCH, [18F]-FDOPA, [18F]-FES, ['$F]-FET, ['$F]-FAPI .

[0027] The synthesis of [13F]-labeled molecules using the method of the present disclosure may be performed manually, or using an automated radiosynthesizer. Homemade or commercially available automated radiosynthesizers are designed to be used in a suitable hot cell that provides adequate radiation shielding to protect the operator from a potential radiation dose. When using a cassette, the automated radiosynthesizer can produce a variety of different radiopharmaceuticals with minimal risk of cross-contamination by simply changing the cassette. This approach also has the advantage of simplifying setup, thereby reducing the risk of operator error, rapidly changing the cassette between runs, and improving regulatory compliance.

BPF, which is the objective of the present invention.

[0028] The term "cassette" means a unit of equipment constructed such that the entire unit removably and interchangeably fits onto an automatic synthesizer device (as defined above) in such a manner that the …— mechanical movement of the 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 insertion of a needle into a vial sealed with an inverted septum or by gas-tight connectors. The cassette is versatile because it typically has multiple positions at which the reagents can be attached, as well as multiple positions suitable for attaching syringes or chromatography cartridges (e.g. for solid phase extraction or EPS). The cassette always includes at least one reaction vessel.

[0029] The present invention does not depend on the details of the above examples and can be applied to any process which uses a nucleophilic [13F] fluorination step.

EXAMPLES

Examples 1 to 12: synthesis of high activity ["°F]-FDG without the presence of a radical scavenger during the labeling step

General procedure

[0030] Automated synthesis of ["°F]-FDG was performed on the synthesizer

AllinOne® (Trasis SA, Belgium). Briefly, fluoride of [°F] obtained from the bombardment of [130]-enriched water was trapped on a QMA light cartridge

More carbonated (130 mg sorbent, QMA was used as received). An aliquot of the eluent containing K2CO3/K222 (300 HL) was used to elute the [13F]-fluoride trapped in the reaction vessel. After evaporation of water by azeotropic drying, an aliquot of the precursor was added to the reactor and labeling was performed at 115 °C for 1.5 min. The intermediate [18F]-FTAG was then trapped and deprotected on the tC18 cartridge, by passing an aliquot of sodium hydroxide solution through the cartridge. An aliquot of water was used to elute the crude ['3FJFDG resulting from the reaction, which was then neutralized with an aliquot of citrate buffer solution. The ['$F]FDG was finally purified through two purification cartridges and sent to the final product vial. To be commercially viable, an uncorrected decay (NCD) yield of at least 65% in ['°F]-FDG is mandatory.

Results

Identification of the cvcle Activity "°F of | Uncorrected yield content y departure (GBq) | EtOH (ppm) | for disintegration (%) [1 | FDGO-250826-AIRGE | 7 | 00 Ma 2 | Foaozsoezsatsoe | KL [ 4 | FOGD280714.A2:SCE | 288 | FDGD280714.ALSCE 082 101 724

Focozowratsce | bone | 0 Toa 3 | Fosozwrioarsce | 61st | 001600 [> | Fooozsrzonrsce | th | 9 | He [10 | FoGozwrrarsce | oah | 001688

LA |_FDGD280703.A1.SCE | 788 | 9 | 6 12 FDGG230606.A1RGE | 760 | 0 | 608

Conclusions

The results show that the yield decreases almost linearly with the starting activity, up to 600 GBg. Beyond this point, the yield drops considerably and is no longer stable anyway. All these variations are due to radiolytic effects that decrease the labeling yield. These examples demonstrate a critical need to stabilize fluorination yields, regardless of the starting activity.

Examples 13-24: Synthesis of ["“F]-FDG in the presence of ethanol during the low activity labeling step

General procedure

[0031] Illustrative examples of the present invention are the automated synthesis of [13F]-FDG on the AllinOne® synthesizer (Trasis SA, Belgium). Briefly, [13F]-fluoride obtained from the bombardment of [180]-enriched water was trapped on a carbonated QMA Plus light cartridge (46 mg of sorbent, QMA was used as received). An aliquot of the eluent containing K2CO3/K222 (300 HL) was used to elute the trapped [13F]-fluoride in the reaction vessel. After evaporation of the water by azeotropic drying, an aliquot of the precursor was added to the reactor, together with different amounts of ethanol, and labeling was carried out at 115°C for 1.5 min. The intermediate ["°F]-FTAG was then trapped and deprotected on the tC18 cartridge by passing an aliquot of sodium hydroxide solution through the cartridge. An aliquot of water was used to elute the crude ['3FJFDG resulting from the reaction, which was then neutralized with an aliquot of citrate buffer solution. The ['$F]FDG was finally purified through two purification cartridges and sent to the final product vial. To be commercially viable, an uncorrected decay (NCD) yield of at least 65% of [13F]-FDG is mandatory.

Results

Departure EEE (MBg) EtOH (ppm) | for disintegration (%) [4 | FDGD-23091-A2SEN | 8 | 1m [16 | FDGD-20013.B1.SEN | 71 | a [16 |Foepzasrseesan 0 | a [6 FDGD-250014.A2:SEN | 4 | 20

BE | 1 10 | m8 2 | FDGQ.230928.A2.A00 180 | za 87

A |Fosozezeasnce | ms | zow | 9 22 |rosazwesaeac | zn | za 2 | FDGD:20019.A1.SEN | 27 [| ao

Conclusion

[0032] These examples prove that it is possible to carry out nucleophilic fluorination of [°F] in the presence of a polar protic solvent, e.g. ethanol, provided that its concentration remains below 30,000 ppm. This result was unexpected and is innovative compared to the state of the art. Below 30,000 ppm, the [13F]-fluoride anions remain fully reactive.

Examples 25-27: Synthesis of ["°F]-FDG in the presence of ethanol during the high-activity labeling step

General procedure

[0033] Automated synthesis of ['$F]-FDG was performed on the synthesizer

AllinOne® (Trasis SA, Belgium). Briefly, fluoride of [°F] obtained from the bombardment of [130]-enriched water was trapped on a QMA light cartridge

More carbonated (46 mg sorbent, QMA was used as received). An aliquot of the eluent containing K2COz/K222 (300 HL) was used to elute the ["$F]-fluoride trapped in the reaction vessel. After evaporation of water by azeotropic drying, an aliquot of the precursor was added to the reactor, along with various amounts of ethanol, and labeling was carried out at 115 °C for 1.5 min.

The ["$F]-FTAG intermediate was then trapped and deprotected on the tC18 cartridge by passing an aliquot of sodium hydroxide solution through the cartridge.

An aliquot of water was used to elute the crude ["°F]FDG resulting from the reaction, which was then neutralized with an aliquot of citrate buffer solution. The ['"°F]FDG was finally purified through two purification cartridges and sent to the final product vial. To be commercially viable, an uncorrected yield for decay (NCD) of at least 65% of [13F]-FDG is mandatory.

Results

Identification of Activity "°F of | Content | Uncorrected yield for cycle start (GBq) | EtOH (ppm) disintegration (%) | FDGD-231000.A1 | 644 | 200 | 60 25 _FDGD-231000.A2 | Toro | 2000

Conclusion

[0034] These examples demonstrate that ethanol can be used to stabilize the 25 yields of high activity [°F] nucleophilic fluorination. At these start-ups, a stabilized and increased production yield of 10 percentage points translates into dozens of additional patient doses, for each production.

Claims (2)

1. Process for stabilizing the production yield of radiotracers labeled with ['3F] by adding a radical scavenger to the reaction medium of the nucleophilic fluorination step with [13F], characterized in that the radical scavenger is ethanol at a concentration of between 5000 and 20000 ppm. 2. The method of claim 1, wherein said ['3F]-labeled radiotracer is selected from the group consisting of [13F]-NaF, ["$F]-FDG, ['8F]-FMISO, [18F]-FLT, ['$F]-FAZA, ['SF]-FCH, ['$F]-FDOPA, ['$F]-FES, ['$F]-FET and [18F]-FAPI derivatives.