Stabilization method for 18f-labeling

Abstract

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

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis. More particularly, this invention relates to methods for synthesizing […]. 18 Methods for labeling molecules with F-, and more particularly methods for stabilizing radiolabeled results at high activity. Background Technology

[0002] Positron emission tomography (PET) and [ 18 F]-mark

[0003] Positron emission tomography (PET) imaging is a minimally invasive and useful imaging technique that can produce three-dimensional images of processes within the body. PET measures physiological function by observing blood flow, metabolism, neurotransmitters, and radiolabeled agents. This imaging technique is based on the indirect detection of gamma rays and radiation emitted by radioactive agents injected into the body.

[0004] Of all the positron emitters that can be used in PET, fluorine-18 ( 18 F) Due to its favorable decay scheme, it is the most ideal. The half-life of this radionuclide (110 min) is due to the multi-step radiolabeling reaction and the... 18 F-labeled tracers allow time for delivery to distant user sites. Furthermore, the short positron emission range (2.3 mm) and ideal decay process (97% positron emission) within tissue contribute to providing high-resolution images. Therefore, the vast majority of PET tracers used clinically are F-labeled tracers. 18 F-labeled molecules, such as [ 18 F] Isotope-labeled glucose, [ 18 F]2-Fluoro-2-deoxy-D-glucose (in the following text [ 18 F]-FDG, which has been widely used in nuclear medicine worldwide, is used for diagnostic research using PET whole-body scanning technology.

[0005] [ 18 F-fluorides are produced by proton irradiation of H2-containing compounds. 18 O's 'enrichment' of water leads to the reaction 18 O(p,n) 18 It is produced by F. Only a small portion [ 18 O] is converted. Then it is separated from the water. 18 F isotopes are processed to produce radiopharmaceuticals.

[0006] In current practice, fluoride recovery is based on the use of anion exchange resins. Recovery involves two steps: extraction and elution. First, anions (not just fluorides) are extracted from the enriched […]. 18 O] is separated from water and captured on the resin. Then, [ 18The anion of [F]-fluoride is eluted into a solution containing water, an organic solvent, a phase transfer agent or activator or phase transfer catalyst (e.g., potassium carbonate-Kryptofix 222 complex (K2CO3-K)). 222 In a mixture of (or tetrabutylammonium salt). 18 The radiochemical recovery yield of F-fluoride is very high, typically exceeding 99%.

[0007] The most commonly used labeling method (called nucleophilic substitution) requires anhydrous or very low water content solutions. Therefore, an evaporation (or drying) step is usually required after recovery to remove excess water. This typically involves multiple azeotropic evaporations of acetonitrile or a low-boiling-temperature organic solvent. Such evaporations take several minutes, and these steps result in highly nucleophilic solutions in a "naked" state. 18 F-fluoride.

[0008] The following [ 18 The [F]-fluorination step can be classified as either aliphatic or aromatic nucleophilic substitution. 18 The prerequisite for [F]-substitution is the presence of a favorable leaving group on the precursor to be labeled. Following these lines of thought, halides Cl, Br, and I, or different types of sulfonates—toluenesulfonates, nosylates, methanesulfonates, and trifluoromethanesulfonates—are most frequently used in radioactive fluorination reactions. After evaporation, the precursor dissolved in a polar aprotic solvent is added to the bare [[] in the reactor. 18 In the F]-fluorine anion, nucleophilic substitution occurs. Typically, radiolabeling requires a heated reactor. Alternatively, nucleophilic substitution can be achieved by loading the precursor solution into a pre-trapping […]. 18 The reaction is carried out on a solid-supported column containing the [F]-fluorine anion. The column can be heated to enhance the nucleophilic substitution reaction. In any case, the yield of the radiolabeling step (e.g., nucleophilic substitution) is crucial to the outcome of the radiotracer synthesis.

[0009] Nucleophilic fluorination reactions are typically carried out in polar aprotic solvents (such as acetonitrile (ACN), N,N-dimethylformamide (DMF), or dimethyl sulfoxide (DMSO)) to increase the solubility of the fluoride salt and the reactivity of the fluoride. Protic solvents (such as water or alcohols) are known to be unsuitable for nucleophilic fluorination reactions because they reduce [the reactivity of the fluoride] through extensive hydrogen bonding and interactions with the partially positive charge of these solvents. 18 The nucleophilicity of [F]-fluorides. Therefore, polar aprotic solvents (such as ACN, DMF, and DMSO mentioned above) have been widely used as these [F]-fluorides. 18 F]- The solvent for radioactive labeling reactions. 18The nucleophilicity of fluorides in polar aprotic solvents is typically enhanced by: selective solvation of the counter cation by the negative end of the polar aprotic solvent dipole and the lack of protons for hydrogen bonding. 18 F]-fluorides exist in a free or naked state. However, to optimize labeling yields, highly efficient aliphatic nucleophilic fluorination and [ 18 F]-Radioactive fluorination method, which utilizes alkali metal fluorides or [ 18F-fluorides, using nonpolar protic tertiary alcohols as reaction solvents (Kim DW, Ahn DS, Oh YH, Lee S., Kil HS, Oh SJ 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 WO2006065038 A1). In this method, tertiary alcohol media (such as tert-butanol and tert-amyl alcohol) greatly enhance the reactivity of alkali metal fluorides.In particular, in the nucleophilic fluorination of base-sensitive compounds such as 1-(2-methanesulfonylethyl)naphthalene and N-5-bromopentanoyl-3,4-dimethoxyaniline, the use of tertiary alcohols significantly reduces the formation of typical byproducts (i.e., olefins, alcohols, or ethers) compared to the use of conventional polar aprotic solvents (Kim DW, Ahn DS, Oh YH, Lee S., Kil HS, 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 DW, Jeong HJ, Lim ST, Sohn MH, Katzenellenbogen JA, Chi DY, Facile nucleophilic [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 DW, Jeong HJ, Lim ST, Sohn MH, Chi D.Y., Facile nucleophilic fluorination by synergistic effect between polymer-supported ionic liquid catalyst and tert-alcohol. Tetrahedron. (2008) 64:4209-4214]. In contrast, the results show that the use of primary or secondary alcohols (such as ethanol) as polar protic solvents leads to the generation of byproducts due to their polarity, thus strongly reducing the labeling yield.

[0010] Because this finding is consistent with conventional [ 18 The expected [18F]-radiofluorination pathway presents a stark contrast; the mechanism of nucleophilic fluorination in nonpolar proton tertiary alcohol solvents has been reported (Kim DW, Jeong HJ, Lim ST, Sohn M.H., Recent Trends in the Nucleophilic [18F]-radiolabeling Method with No-carrier-added [18F]fluoride. Nucl Med Mol Imaging. (2010) 44:25-32). The authors propose the following mechanism: coordination with bulky tertiary alcohols... 18Limited solvation of F-fluorides (referred to as “flexible” fluorides) can make fluorides particularly good nucleophiles in this medium; the reactivity of leaving groups can be enhanced by hydrogen bonding between the oxygen atoms of the leaving groups of sulfonate esters and the tertiary alcohol solvent; side reactions such as elimination, hydroxylation, and intramolecular alkylation can be suppressed by a proton environment, especially when using base-sensitive precursors (Kim DW, Jeong HJ, Lim S.T., Sohn MH, Katzenellenbogen JA, Chi DY, Facile nucleophilic fluorination reaction using tert-alcohols as a reaction medium: significantly enhanced reactivity of alkali metal fluorides and improved selectivity [Using tertiary alcohols as a reaction medium: significantly enhanced reactivity of alkali metal fluorides and improved selectivity]. J Org Chem [Organic Chemistry Journal]. (2008) 73:957-962; Kim DW, Jeong HJ, Lim S.T., Sohn MH, Chi DY, Facile nucleophilic fluorination by synergistic effect between polymer-supported ionic liquid catalyst and tert-alcohol. Tetrahedron (2008) 64:4209-4214. More recent papers have demonstrated that, as a result of the preparation of tetrabutylammonium tetratert-butanol coordinated fluoride TBAF(t-BuOH)4 from commercially available TBAF in t-BuOH, “flexible” fluorides can be formed during fluorination treatment in tert-alcohol media.This TBAF(t-BuOH)4 also exhibits good performance in nucleophilic fluorination due to its desirable properties as a fluoride source, such as its dehydrated state under anhydrous reaction conditions, low hygroscopicity, good solubility in organic solvents, and good nucleophilicity at low basicity (Kim DW, Jeong HJ, Lim ST, Sohn MH Tetrabutylammonium tetra(tert-butyl alcohol)-coordinated fluoride as a facile fluoride source [Tetrabutylammonium tetra(tert-butyl alcohol)-coordinated fluoride as a facile fluoride source]. Angew Chem Int Ed Engl [Applied Chemistry International Edition]. (2008) 47:8404-8406). To achieve this 'flexible' fluoride, the tertiary alcohol must be predominantly present in the reaction medium, for example, as a solvent itself rather than as an auxiliary agent or catalyst. Clearly, this 'flexible' fluoride cannot be obtained using polar protic solvents (such as primary or secondary alcohols), primarily due to their high intrinsic polarity.

[0011] Protecting groups are often needed to eliminate acidic protons in a molecule, which will reduce […]. 18 The nucleophilicity of [F]-fluorides. If a protecting group has been used, it 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.

[0012] Radiation decomposition

[0013] Due to the above [ 18 The short half-life of F isotopes, 18 F-labeled radiotracers must be produced at relatively high activities to allow for decay during delivery from the manufacturing facility to the patient. A major stability problem for radiopharmaceuticals is known to be radiodegradation, which can be self-radiative decomposition (self-destruction caused by its own radiation) and / or attack by free radicals formed from radiation of environmental materials. 18 The radiative decomposition, or more specifically, the self-radiative decomposition, of [F]-FDG has been extensively reviewed, and primarily produces free [ 18[18F]-fluoride ions (Jószai I., Svidró M., Pótári N., Recommendations for selection of additives for stabilization of [18F]FDG. Appl Radiat Isot. (2019) 146:78-83) and free radicals—this is due to the reaction of ionizing radiation with water (Buriova E., Macasek F., Kropacek M., Prochazka L., Autoradiolysis of 2-deoxy-2-[18F]fluoro-D-glucoseradiopharmaceutical. J Radioanal Nucl Chem. (2005) 3:595-602).

[0014] Several strategies exist to reduce radiodecomposition: a common and well-documented strategy is to use radiation stabilizers to stabilize the final products. 18 The most well-known and commonly used radiation stabilizer for [F]-FDG is ethanol. Adding ethanol to formulations of the final product at concentrations of 0.1%–0.4% has been shown to effectively stabilize [F]-FDG with activities up to 25 GBq / ml. 18[F]-FDG lasts up to 16 hours (Dantas NM, Nascimento JE, Santos-Magalhães NS, Oliveira ML, Radiolysis of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and the role of ethanol, radioactive concentration and temperature of storage [2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and the role of ethanol, radioactive concentration and temperature of storage]. Appl Radiat Isot [Applied Radiation and Isotopes]. (2013) 72:158-62; Fawdry RM, Radiolysis of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and the role of reductant stabilisers [2-[18F]fluoro-2-deoxy-D-glucose (FDG) and the role of reductant stabilizers]. Appl Radiat Isot [Applied Radiation and Isotopes]. (2007) 65:1193-201; Jacobson MS, Dankwart HR, Mahoney DW, Radiolysis of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and the role of ethanol and radioactive concentration. Appl Radiat Isot. (2009) 67:990-5; Walters LR, Martin KJ, Jacobson MS, Hung JC, Mosman EA, Stability evaluation of 18F-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 [18F]FDG produced by an alkaline hydrolysis on solid support under stringent conditions. Appl Radiat Isot. (2002) 56:871-5; Jószai I., Svidró M., Pótári N., Recommendations for selection of additives for stabilization of [18F]FDG. Appl Radiat Isot. (2019) 146:78-83; Holler JG, Renmælmo B., Fjellaksel R., Stability evaluation of [18F]FDG: literature study, stability studies [[18F]FDG Stability Assessment: Literature Review, Stability Studies from Two Different PET Centers and Future Recommendations]. EJNMMI Radiopharmacy and Chemistry (2022) 7:2-20.

[0015] The dilution factor of the product as a stabilizer must also be considered, but dilution is limited due to the maximum injection volume, and radioactive stabilizers can also be considered (Jiménez Romero IR, Roca Engronyat M., Campos Añón F., Cordero Ramajo J., Liarte Trías I., Benítez Segura A., Bajén Lázaro M., Ferrán Sureda N., Puchal Añé R., Gámez Cenzano C., Influence of radioactive concentration and storage time on radiochemical purity of 18F-FDG. Rev Esp Med Nucl [Spanish Journal of Nuclear Medicine]. (2006) 45:20-5; Hjelstuen OK, Svadberg A., Olberg DE, Rosser M., Standardization of fluorine-18 manufacturing processes: new scientific challenges for PET). [Standardization of Fluorine-18 Manufacturing Methods: New Scientific Challenges for PET]. Eur J PharmBiopharm (European Journal of Pharmaceutics and Biopharmaceutics). (2011) 78:307-13.

[0016] The problem to be solved

[0017] While the aforementioned prior art studies only provide solutions for enhancing the stability of the final radiolabeled product, it is worthwhile to address radiation decomposition upstream, primarily during the labeling step. The primary focus should be on maximizing […] during the radiolabeling step. 18 The incorporation of F-fluoride significantly increases production yield, the number of injectable doses produced per batch, and thus reduces the cost of the dose to be applied.

[0018] Furthermore, since PET imaging depends on the [ 18 The detection of positrons emitted by the decay of F-labeled radioactive tracers, therefore [ 18The higher incorporation rate of the precursor molecule leads to a higher specific activity of the radiotracer. Radiotracers with high specific activity offer better sensitivity and accuracy in detecting target biological processes or molecules in vivo. Furthermore, the higher incorporation rate allows for the synthesis of radiotracers with lower mass cold (non-radioactive) components. This is important because even small-mass carrier molecules can interfere with biological processes under investigation, potentially leading to biased images or undesirable side effects. Finally, radiotracers with high specific activity provide clearer PET images. This improved resolution allows for better localization and quantification of biological targets, thus contributing to accurate diagnosis and treatment monitoring.

[0019] Therefore, maximize [ 18 The incorporation rate of [F] into the precursor molecule is crucial for producing high-quality radiotracers with optimal sensitivity, accuracy, and imaging resolution, and is also essential for more efficient patient outcomes, as it leads to improved radiotracer production results. However, achieving high incorporation rates, especially at high activity levels, is challenging due to the increased likelihood of radiodecomposition (where high-energy radiation breaks chemical bonds in the precursor molecule), reaction complexity, and short reaction times. Overcoming these challenges requires careful optimization of reaction conditions.

[0020] Purpose of the invention

[0021] This invention aims to achieve this through nucleophilic [ 18 During the fluorination step, a free radical scavenger is used to avoid […]. 18 The decomposition reaction of the radiosynthetic intermediate used in the synthesis of F-labeled radiotracers, i.e., radiodecomposition caused by high radioactive concentrations. In other words, the present invention aims to stabilize [F-labeled radiotracers obtained through nucleophilic aliphatic or aromatic substitution]. 18 Radiochemical yield of radiochemical synthesis of F-labeled radioactive tracers—regardless of the initial level of radioactivity used. Detailed Implementation

[0022] This invention relates to […] 18 Nucleophilic synthesis of F-labeled radiotracers 18 During the F-fluorination step, free radical scavengers are used to stabilize the radioactive decomposition of radiosynthetic intermediates (including cold intermediates, such as precursors to be radiolabeled).

[0023] Based on the precursor to be labeled, nucleophilic [ 18 The fluorination step can be classified as either aliphatic or aromatic. The former is found in […]. 18 In the synthesis of F-FDG. 18The typical synthesis of F-FDG is a two-step process consisting of two chemical reactions: nucleophilic reaction of the mannose trifluoromethanesulfonate precursor (1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose) 18 [F]-fluorination, followed by hydrolysis of several protecting groups. After several drying steps, the substitution reaction is completed in a polar aprotic solvent (e.g., acetonitrile). At high activities, the substitution reaction can lead to various byproducts due to radiodecomposition, which negatively impacts production yields (Examples 1-12). This invention aims to stabilize [F] by adding a free radical scavenger to the reaction vessel to stabilize the labeling yield—regardless of the initial activity. 18 Results of F-labeled radioactive tracer production.

[0024] Through nucleophilic [ 18 F]-fluorination process to produce [ 18 [F]-tagged molecules begin to be produced in a cyclotron. 18 F] Fluorides. Regarding cyclotrons [ 18 Two key characteristics of F-fluoride production are the proton beam energy and beam current used. These two factors, along with the target volume, determine how much [fluoride] can be produced in a given time period. 18 F - Fluoride content, i.e., activity. To some extent, the higher the energy and beam current, the greater the fluoride production. All commercially available cyclotrons today are capable of producing beams with a current of at least 50 μA. [For use in...] 18 Liquid targets produced by [F] typically do not operate above 100 μA due to limitations imposed by the dissipation of heat generated during irradiation. Typically, a given target at a given operating pressure has an optimal current at which the production rate is highest. This does not necessarily have to be the highest possible current. The most powerful and efficient cyclotrons today can produce up to 1480 GBq of [F]. 18 F]-fluorides. Knowing that radiolysis can occur at activities as low as approximately 3.5 GBq, it is crucial to find solutions resistant to radiolysis at such activity levels to stabilize labeling yields and thus stabilize [F]. 18 The production results of F-labeled radioactive tracers—regardless of the initial activity. Therefore, in the following text, the term "high activity" for solutions will refer to solutions with an activity greater than 37 GBq, preferably greater than 100 GBq, and more preferably greater than 500 GBq.

[0025] In order to stabilize the above yield, the inventors unexpectedly discovered that the free radical scavenger substance, if added at a specific concentration, can be a polar protic compound (Examples 13-31).

[0026] According to the present invention, the free radical scavenger is an alcohol. In some preferred embodiments, the free radical scavenger is a primary or secondary alcohol, more preferably a primary alkyl alcohol, and even more preferably methanol or ethanol, wherein ethanol is still preferred.

[0027] In some embodiments, the [18F]-labeled radioactive tracer is selected from, but not limited to, […]. 18 F]-NaF, [ 18 F]-FDG, [ 18 F]-FMISO, [ 18 F]-FLT, [ 18 F]-FAZA, [ 18 F]-FCH, [ 18 F]-FDOPA, [ 18 F]-FES, [ 18 F]-FET, [ 18 F]-FAPI derivatives.

[0028] In some preferred embodiments, the concentration of the free radical scavenger ranges from 5,000 ppm to 30,000 ppm.

[0029] In some other preferred embodiments, the concentration of the free radical scavenger ranges from 10,000 ppm to 25,000 ppm.

[0030] In some other preferred embodiments, the concentration of the free radical scavenger ranges from 5,000 to 15,000 ppm.

[0031] In some other preferred embodiments, the concentration of the free radical scavenger ranges from 15,000 to 25,000 ppm.

[0032] In some other preferred embodiments, the concentration of the free radical scavenger ranges from 15,000 to 20,000 ppm.

[0033] In some other preferred embodiments, the concentration of the free radical scavenger ranges from 15,000 to 28,000 ppm.

[0034] In some preferred embodiments, [ 18 F-labeled radioactive tracers are high-activity [ 18 F]-FDG, a free radical scavenger, is ethanol in the concentration range of 10,000 to 20,000 ppm, with a stabilized non-decay corrected yield of over 65%.

[0035] In some preferred embodiments, [ 18 F-labeled radioactive tracers are [ 18F]-FDG, the free radical scavenger is ethanol, and the concentration range of the free radical scavenger is 5000 to 20000 ppm.

[0036] Synthesized using the method disclosed herein 18 [F]-labeled molecules can be produced manually or using an automated radiosynthesizer. Homemade or commercially available automated radiosynthesizers are designed for use in a suitable hot chamber that provides adequate radiation shielding to protect the operator from potential radiation doses. When using cartridges, the automated radiosynthesizer can produce a variety of different radiopharmaceuticals with minimal risk of cross-contamination by simply changing the cartridges. This method also has the advantage of simplified setup, thereby reducing the risk of operator error, allowing for rapid cartridge changes between runs, and improving compliance with GMP regulations, which is the subject of this invention.

[0037] The term "cassette" refers to a device unit constructed such that the entire unit can be removably and replaceably mounted on an automated synthesizer apparatus (as defined above) in such a way that the mechanical movement of the synthesizer's moving parts is controlled from outside the cassette for its operation. A suitable cassette consists of a linear array of valves, each connected to a port that can be connected to a reagent or vial by needle puncture and sealing with an inverted diaphragm or via a hermetically sealed connector. The cassette is versatile, as it typically has several locations for attaching reagents and several locations suitable for attaching syringes or chromatographic columns (e.g., for solid-phase extraction or SPE). The cassette always includes at least one reaction vessel.

[0038] This invention does not depend on the details of the above examples and should be applied to the use of nucleophiles. 18 Any method of the F-fluorination step.

[0039] Example

[0040] Examples 1-12: Synthesis with high activity in the absence of free radical scavengers during the labeling step [ 18 F]- FDG

[0041] General Program

[0042] Performed on an AllinOne® synthesizer (Trasis SA, Belgium) 18 Automated synthesis of [F]-FDG. In short, it involves the bombardment enrichment of [F]-FDG. 18 O]-Water obtained[ 18 F-fluoride was captured on a carbonate-type QMA Plus light column (130 mg adsorbent, QMA used as received). A K₂CO₃ / K₂O₃ adsorbent was used. 222 Equal portions (300 µL) of the eluent will be used to capture [18 [F]-fluoride was eluted into the reaction vessel. After evaporation of water via azeotropic drying, aliquots of the precursor were added to the reactor and labeled at 115°C for 1.5 min. The intermediate [F]-fluoride was then [eluted]. 18 F-FTAG was trapped on a C18 column and deprotected by passing an aliquot of sodium hydroxide solution through the column. An aliquot of water was used to elute the crude [products] generated during the reaction. 18 F]FDG, which was then neutralized with an aliquot of citrate buffer solution. Finally, [ 18 F]FDG was purified using two purification columns and then sent to a final product vial. For commercial viability, [ 18 The non-decay-corrected (NDC) yield of F-FDG must be at least 65%.

[0043] result

[0044]

[0045] in conclusion

[0046] The results showed that, up to 600 GBq, the yield decreased almost linearly with the initial activity. Above this point, the yield decreased significantly and became completely unstable in all cases. All these variations were due to the radiation decomposition effect that reduced the labeling yield. These examples demonstrate the urgent need for stable fluorination yields—regardless of the initial activity.

[0047] Examples 13-24: Synthesis at low activity in the presence of ethanol during the labeling step [ 18 F]-FDG

[0048] General Program

[0049] The illustrative embodiments of the present invention were performed on an AllinOne® synthesizer (Traceys AG, Belgium). 18 Automated synthesis of [F]-FDG. In short, it involves the bombardment enrichment of [F]-FDG. 18 O]-Water obtained[ 18 F-fluoride was captured on a carbonate-type QMA Plus light column (46 mg adsorbent, QMA used as received). A K₂CO₃ / K₂O₃ adsorbent was used. 222 Equal portions (300 µL) of the eluent will be used to capture [ 18 [F]-fluoride was eluted into the reaction vessel. After evaporation of water by azeotropic drying, aliquots of the precursor were added to the reactor along with varying amounts of ethanol and labeled at 115°C for 1.5 min. The intermediate [F]-fluoride was then [eluted]. 18F-FTAG was trapped on a C18 column and deprotected by passing an aliquot of sodium hydroxide solution through the column. An aliquot of water was used to elute the crude [products] generated during the reaction. 18 F]FDG, which was then neutralized with an aliquot of citrate buffer solution. Finally, [ 18 F]FDG was purified using two purification columns and then sent to a final product vial. For commercial viability, [ 18 The non-decay-corrected (NDC) yield of F-FDG must be at least 65%.

[0050] result

[0051]

[0052] in conclusion

[0053] These examples demonstrate that nucleophilicity can be performed in the presence of a polar protic solvent (e.g., ethanol) at a concentration below 30,000 ppm. 18 F-fluorination. This result is unexpected and innovative compared to existing technologies. Below 30,000 ppm, [ 18 The F-fluorine anion remains fully reactive.

[0054] Examples 25-31: Synthesis of [18F]-FDG with high activity in the presence of ethanol during the labeling step

[0055] General Program

[0056] Performed on an AllinOne® synthesizer (Traceys AG, Belgium) 18 Automated synthesis of [F]-FDG. In short, it involves the bombardment enrichment of [F]-FDG. 18 O]-Water obtained[ 18 F-fluoride was captured on a carbonate-type QMA Pluslight column (46 mg adsorbent, QMA used as received). A K₂CO₃ / K₂O₃ adsorbent was used. 222 Equal portions (300 µL) of the eluent will be used to capture [ 18 [F]-fluoride was eluted into the reaction vessel. After evaporation of water by azeotropic drying, aliquots of the precursor were added to the reactor along with varying amounts of ethanol and labeled at 115°C for 1.5 min. The intermediate [F]-fluoride was then [eluted]. 18 F-FTAG was trapped on a C18 column and deprotected by passing an aliquot of sodium hydroxide solution through the column. An aliquot of water was used to elute the crude [products] generated during the reaction. 18 F]FDG, which was then neutralized with an aliquot of citrate buffer solution. Finally, [ 18F]FDG was purified using two purification columns and then sent to a final product vial. For commercial viability, [ 18 The non-decay-corrected (NDC) yield of F-FDG must be at least 65%.

[0057] result

[0058]

[0059] in conclusion

[0060] These examples demonstrate that ethanol can be used to stabilize nucleophiles at high activity levels. 18 F-fluorination yield. At this initial activity, a stabilization and 10 percentage point increase in production yield translates to an increase of dozens of patient doses per production.

[0061] Examples 32-34: Synthesis at low activity with ethanol as a solvent during the labeling step [ 18 F]- FDG

[0062] General Program

[0063] Performed on an AllinOne® synthesizer (Traceys AG, Belgium) 18 Automated synthesis of [F]-FDG. In short, it involves the bombardment enrichment of [F]-FDG. 18 O]-Water obtained[ 18 F-fluoride was captured on a carbonate-type QMA Pluslight column (46 mg adsorbent, QMA used as received). The captured [ ]-fluoride was eluented using aliquots (300 µL) containing K₂CO₃ / K₂₂. 18 [F]-fluoride was eluted into the reaction vessel. After evaporation of water via azeotropic drying, aliquots of the precursor dissolved in ethanol were added to the reactor and labeled over a period of 1.5 min at 115°C. The intermediate [F]-fluoride was then added. 18 F-FTAG was trapped on a C18 column and deprotected by passing an aliquot of sodium hydroxide solution through the column. An aliquot of water was used to elute the crude [products] generated during the reaction. 18 F]FDG, which was then neutralized with an aliquot of citrate buffer solution. Finally, [ 18 F]FDG was purified using two purification columns and then sent to a final product vial.

[0064]

[0065] in conclusion

[0066] These examples demonstrate that polar protic solvents (such as primary alcohols, like ethanol) cannot be used as solvents for nucleophilic reactions. 18F-fluorination, while in this invention, ethanol is kept at a very limited concentration below 30,000 ppm.

Claims

1. A method that utilizes nucleophilic [ 18 Free radical scavengers are added to the reaction medium of the [F]-fluorination step to stabilize it. 18 A method for producing F-labeled radioactive tracers, wherein... The free radical scavenger is an alcohol.

2. The method as described in claim 1, wherein, The [18F]-labeled radioactive tracer is selected from the group consisting of: 18 F]-NaF, [ 18 F]-FDG, [ 18 F]-FMISO, [ 18 F]-FLT, [ 18 F]-FAZA, [ 18 F]-FCH, [ 18 F]-FDOPA, [ 18 F]-FES, [ 18 F]-FET and [ 18 F]-FAPI derivatives.

3. The method as described in claim 1, wherein, The free radical scavenger is a primary or secondary alcohol.

4. The method as described in claim 1 or 3, wherein, The free radical scavenger is a primary alcohol.

5. The method of claim 4, wherein, The free radical scavenger is a primary alkyl alcohol.

6. The method of claim 4, wherein, The free radical scavenger is methanol or ethanol.

7. The method of claim 4 or 6, wherein, The free radical scavenger is ethanol.

8. The method of claim 1, wherein, The concentration range of this free radical scavenger is 5,000 to 30,000 ppm.

9. The method of claim 1, wherein, The concentration range of this free radical scavenger is 10,000 to 25,000 ppm.

10. The method of claim 1, wherein, The concentration range of this free radical scavenger is 5000 to 15000 ppm.

11. The method of claim 1, wherein, The concentration range of this free radical scavenger is 15,000 to 25,000 ppm.

12. The method of claim 1, wherein, The concentration range of this free radical scavenger is 15,000 to 20,000 ppm.

13. The method of claim 1, wherein, The concentration range of this free radical scavenger is 15,000 to 28,000 ppm.

14. The method of claim 1, wherein, Should[ 18 F-labeled radioactive tracers are high-activity [ 18 F]-FDG, a free radical scavenger with a concentration range of 10,000 to 20,000 ppm and a non-decay corrected yield of over 65%.

15. The method of claim 1, wherein, Should[ 18 F-labeled radioactive tracers are [ 18 F]-FDG, the free radical scavenger is ethanol, and the concentration range of the free radical scavenger is 5000 to 20000 ppm.

Images