Isotopologues of Potassium 2,2,2-Trifluoroethoxide for Applications in Positron Emission Tomography and Beyond

doi:10.21203/rs.3.rs-3922094/v1

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Isotopologues of Potassium 2,2,2-Trifluoroethoxide for Applications in Positron Emission Tomography and Beyond

https://doi.org/10.21203/rs.3.rs-3922094/v1

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The 2.2.2-trifluoroethoxy group increasingly features in drugs and potential tracers for biomedical imaging with positron emission tomography (PET). Herein, we describe a novel rapid and metal-free conversion of fluoroform with paraformaldehyde into highly reactive potassium 2,2,2-trifluoroethoxide (CF₃CH₂OK) and demonstrate robust applications of this synthon in one-pot, two-stage 2,2,2-trifluoroethoxylations of both aromatic and aliphatic precursors. Moreover, we show that these novel transformations translate easily to fluoroform that has been labeled with either carbon-11(t_1/2 = 20.4 min) or fluorine-18 (t_1/2 = 109.8 min), so allowing the appendage of complex molecules with a no-carrier-added ¹¹C- or ¹⁸F- 2,2,2-trifluoroethoxy group. This provides enormous scope to provide new candidate PET tracers with radioactive and metabolically stable 2,2,2-trifluoroethoxy moieties. We also exemplify syntheses of isotopologues of potassium 2,2,2-trifluoroethoxide and show their utility for stable isotopic labeling which can be of further benefit for drug discovery and development.

Physical sciences/Chemistry

Health sciences/Molecular medicine

Trifluoromethylation finds extensive utility in medical chemistry and has led to many drug-like compounds with improved pharmacokinetic and physicochemical properties (1). Over the past decade, substantial advances have been made in trifluoromethylation methods (2–4). Fluoroform (HCF₃) is a major industrial byproduct and now gains attention as an affordable and atom-efficient source of the trifluoromethyl group (CF₃) (5, 6). Strategies for installing a trifluoromethyl group from fluoroform deploy nucleophilic or metal-mediated conversions (Fig. 1A). Nucleophilic trifluoromethylations rely on the deprotonation of fluoroform in the presence of a strong base to generate the reactive trifluoromethyl anion (7), which can subsequently undergo reaction with a wide range of electrophiles (8). Metal-mediated trifluoromethylation reactions(9) convert fluoroform into a more stable copper(I) (CuCF₃; 10) or silver(I) (AgCF₃;11) derivative, which can engage productively in diverse reactions.

Positron emission tomography (PET) is a molecular imaging modality that now plays a vital role in biomedical research, drug discovery, disease staging, and disease diagnosis (12,13). PET tracers are produced at time of need and the majority are labeled with cyclotron-produced short-lived carbon-11 (t_1/2 = 20.4 min) or fluorine-18 (t_1/2 = 109.8 min) (14–16). ¹¹C-Labeled tracers are valuable for studies that demand multiple imaging sessions within the same day, whereas ¹⁸F-labeled tracers may be distributed to remote PET imaging facilities that lack an on-site cyclotron and radiochemistry facility. The production of PET tracers for biomedical applications relies on straightforward radiolabeling strategies. For carbon-11, [¹¹C]iodomethane and [¹¹C]methyl triflate are of foremost importance for tracer syntheses through reactions with carbon and heteroatom electrophiles (14–17). For fluorine-18, nucleophilic substitution on appropriate precursors with [¹⁸F]fluoride is widely used(18,19) (Fig. 1C). However, these and many other methods are limited with regards to the chemotypes that can be labeled and to the possible molecular positions that are open to labeling. Because of tracer metabolism, the position of radiolabel can be a key determinant of PET tracer efficacy (20).

There is an ongoing need to expand the range of chemotypes that may be considered as potential PET tracers through the development of novel labeling synthons and methods (21). Methods to label a single tracer with either carbon-11 or fluorine-18 normally require different non-radioactive precursors and entail major synthesis campaigns that may consume excessive time and resources. A more efficient approach is to take advantage of chemical moieties that contain both carbon-11 and fluorine-18 labeling sites and offer labeling via a single precursor. This strategy can simplify the PET radiotracer development process and more effectively address design requirements. In this respect, ¹¹C and ¹⁸F-labeled fluoroforms (22–24) are attractive synthons because they are readily accessible through rapid on-line syntheses as precursors to putatively metabolically stable trifluoromethyl groups (Fig. 1C). Nonetheless, these labeling synthons have been applied almost exclusively to labeling arenes. Application to labeling non-functionalized aliphatic substrates has not been demonstrated.

The 2,2,2-trifluoroethoxy group(25) has notable metabolic stability(26) and moderate lipophilicity and is found in numerous biologically active compounds(27‒30). Several PET radiotracers feature a 2.2.2 trifluoroethoxy moiety (e.g., tracers for COX-1 (31, 32), tauopathy (33‒36), and Huntington aggregates (37). Installation of a radiolabeled 2,2,2-trifluoroethoxy group in such tracers has been approached through either nucleophilic addition of [¹⁸F]fluoride to a geminal difluorovinyl precursor (31, 33, 36, 37) or alkylation of a phenoxy precursor with [¹⁸F]2.2.2-trifluoroethoxy tosylate (31, 35, 38). However, both methods suffer from limited substrate scope and low molar activity (ratio of radioactivity to mass of tracer isotopologues) that may make the derived tracers unsuitable for application (20,39).

Herein, we describe a novel, rapid and metal-free conversion of fluoroform into highly reactive potassium 2,2,2-trifluoroethoxide (CF₃CH₂OK) and demonstrate robust applications of this synthon in one-pot, two-stage 2,2,2-trifluoroethoxylations of both aromatic and aliphatic precursors (Fig. 1B). Moreover, we show that this novel transformation translates easily to both carbon-11 and fluorine-18 chemistry so allowing the appendage of complex molecules with ¹¹C- or ¹⁸F- labeled 2,2,2-trifluoroethoxy groups (Fig. 1D). We also exemplify syntheses of isotopologues of potassium 2,2,2-trifluoroethoxide and show their utility for stable isotopic labeling.

Nucleophilic addition of fluoroform to aldehydes to produce carbinols is well-known (40). However, the reaction of fluoroform with the simplest aldehyde, formaldehyde, has not been explored. We considered that this reaction should produce a very useful reagent, 2,2,2-trifluoroethoxide. Because of the toxicity and volatility of formaldehyde (41), we decided to explore solid paraformaldehyde as an alternative for producing 2,2,2-trifluoroethoxide. Treatment of fluoroform as limiting reagent with a mixture of paraformaldehyde and t-BuOK in DMF produced 2,2,2-trifluoroethanol in 41% yield after water quench (Table S1, entry 1). Under optimal conditions, fluoroform was converted into 2,2,2-trifluoroethanol in 88% yield within 30 minutes (Table S1, entry 13). Increasing the reaction time did not improve the conversion appreciably (Table S1, entries 11 and 12). Other bases or solvents adversely affected yield (Table S1, entries 14–18).

We next tested the reactivity of the putative intermediate, potassium 2,2,2-trifluoroethoxide, by treatment with 2-chloropyrimidine. To our delight, reaction proceeded smoothly at room temperature to afford 2-(2,2,2-trifluoroethoxy)pyrimidine (1) in 71% yield within 2 hours (Fig. 2A). However, treatment of potassium 2,2,2-trifluoroethoxide with 1-fluoronaphthalene gave only trace 1-(2,2,2-trifluoroethoxy)naphthalene (2), even at elevated temperature. We considered that an aryl hypervalent iodine center in an aryliodonium ylide might show more reactivity. Indeed, treatment of potassium 2,2,2-trifluoroethoxide with naphthalen-1-yl iodonium-(2,2-dimethyl-1,3-dioxane-4,6-dione)ylide at 60 ^oC produced 2 in 63% yield (Fig. 2A). Thus, gratifyingly, we had succeeded in converting stoichiometric amounts of fluoroform into a useful synthon, potassium 2,2,2-trifluoroethoxide in high yield and in showing the utility of this synthon for trifluoroethoxylation of homoarene and heteroarene under mild conditions. We anticipate that this new metal-free transformation can find wide application in fluorine chemistry. Indeed, we readily produced several trifluoroethoxy compounds in high yields by this chemistry as standards for use in the remainder of this study (see Supporting Information).

We next aimed to explore this synthetic methodology for robust broad-scope radio-trifluoroethoxylations as a potentially new route to PET tracers. For this purpose, we routinely [¹¹C]fluoroform by CoF₃-mediated fluorination of cyclotron-produced [¹¹C]methane (22). Treatment of [¹¹C]fluoroform (37–296 MBq) with a mixture of t-BuOK (50 µmol) and paraformaldehyde (17 µmol) in DMF for only 3 minutes at room temperature gave an excellent yield (88%) of ¹¹CF₃CH₂OH upon hydrolysis of the putative intermediate (Fig. 2B, entry 1). Increasing the reaction time to 5 minutes only slightly increased the yield. A larger quantity of paraformaldehyde (50 µmol) afforded ¹¹CF₃CH₂OH in 97% yield. The yield of ¹¹CF₃CH₂OH was quantitative when [¹¹C]fluoroform was treated with 1: 2 molar mixture of paraformaldehyde and t-BuOK for 4 minutes (Fig. 2B, entry 5). These reaction conditions were therefore deemed optimal. This success encouraged us to test the efficacy of ¹¹CF₃CH₂OK for introducing the ¹¹C-trifluoromethyl moiety into a wide range of compounds.

First, we examined the reactivity of ¹¹CF₃CH₂OK towards heteroarenes. To our delight, ¹¹CF₃CH₂OK reacted at room temperature to produce a wide range of desired ¹¹C-2,2,2-trifluoroethoxy heteroarenes in moderate to excellent yields within just 1 minute (Fig. 3A). Attractive features to emerge from this labeling protocol were: 1) the ¹¹CF₃CH₂OK, can be used without isolation; 2) reaction conditions are mild and rapid; 3) substrate scope is broad, and encompasses pyridines, pyrimidines, pyrazine, thiazoles, triazines, quinolines, and isoquinolines; 4) in addition to halides (F, Cl, and Br), leaving groups such as nitro ([¹¹C]4) and methyl sulfone ([¹¹C]9) are highly effective; 5) functional group tolerance is high, with aldehyde ([¹¹C]3), bromo ([¹¹C]4, [¹¹C]6), nitrile ([¹¹C]5), methoxy ([¹¹C]7), and Boc protection ([¹¹C]9) all well tolerated. Heteroarenes having 1 to 3 nitrogen atoms ([¹¹C]1, [¹¹C]3–[¹¹C]14) were compatible with the reaction conditions and afforded the desired ¹¹C-labeled products in acceptable yields (21–94%). Furthermore, the late-stage ¹¹C-trifluoroethoxylation of complex biomolecules was highly effective as shown by the labeling of analogues of several drug-like compounds [Imiquimod ([¹¹C]15), Milrinone ([¹¹C]18)], drug precursors [Erlotinib ([¹¹C]19), Canagliflozin ([¹¹C]20), Pazopanib ([¹¹C]21), Palbociclib ([¹¹C]22)], the herbicide Clopyralid ([¹¹C]17), and a purine derivative ([¹¹C]16)] in moderate to very good yields. Notably, ¹¹C-trifluoroethoxylation occurred preferentially at the more electron-deficient site (e.g., the ortho vs meta pyridinyl site for [¹¹C]17) or aryl ring (e.g., the pyridinyl vs homoarene ring in [¹¹C]6 and [¹¹C]20).

We found that homoarene precursors with common leaving groups were more challenging for ¹¹C-trifluoroethoxylation than the reactive heteroarenes (42). We anticipated that the use of a more powerful hypervalent aryliodonium leaving group (43, 44) could alleviate this issue. We opted to explore this possibility for the one-pot ¹¹C-trifluoroethoxylation of homoarene substrates. First, we screened conditions for the reaction of [¹¹C]potassium 2,2,2-trifluoroethoxide with iodonium ylide derived from Meldrum’s acid (naphthalen-1-yl(2,4,6-trimethoxyphenyl)iodonium tosylate) (Table S3). We found that treating a mixture of [¹¹C]CF₃CH₂OK with the iodonium salt precursor (55 µmol) in DMF at 60 ^oC for 3 minutes gave a high and optimal yield of the desired [¹¹C]2 (87%; Table S3, entry 2). The 2,4,6-trimethoxyphenyl group served as an effective aryl spectator ring; no [¹¹C]1,3,5-trimethoxy-(2-(2,2,2-trifluoroethoxy))benzene, was produced. An increase in temperature did not improve the yield of [¹¹C]2. Reduction in precursor amount reduced yield. Given the high yield obtained for [¹¹C]2 with this approach under optimal conditions, we proceeded to explore substrate scope. Substituent electronics had substantial influence on reaction yields ([¹¹C]23–[¹¹C]32). Electron-withdrawing groups in ortho and para position gave high yields for the ¹¹C-trifluoroethoxylation (Fig. 3B). ¹¹C-Trifluorethoxylation yields were lower for substrates with para- electron-donating or meta- electron-withdrawing groups. Novel cross-coupling synthons, [¹¹C]24–[¹¹C]27, were obtained in useful yields. We drew attention to the syntheses of [¹¹C]26 and [¹¹C]28, where mesityl was used as the partner aryl ring in the iodonium salt precursor. ¹¹C-Trifluoroethoxylation was directed to the other aryl ring. This is an interesting observation because here ring chemoselectivity is opposite to that seen for the non-copper mediated radiofluorination of aryl(mesityl)iodonium salts (45).

We also explored aryliodonium ylides as precursors. ¹¹C-Trifluoroethoxylation of three model ylides gave [¹¹C]33–[¹¹C]35, in moderate to high yields. Moreover, [¹¹C]36, an analogue of the antidiabetic drug emplagliflozin (®Jardiance) was also obtained in moderate yield (47%) from an ylide. These are the first examples of iodonium ylides serving as precursors for the trifluoroethoxylation reaction. In addition, two activated fluoroarenes, with ortho electron-deficient aryl rings, gave [¹¹C]37 and [¹¹C]38 in moderate to good yields where fluoride was the leaving group.

Fluorine-18 labeling of PET tracers at aliphatic carbon by nucleophilic substitution of a good leaving group with [¹⁸F]fluoride (19) can often lead to an [¹⁸F]fluoroalkyl group that is vulnerable to radiodefluorination in vivo and to accumulation of [¹⁸F]fluoride ion in the bone including skull. This can hamper accurate quantification of tracer uptake, especially in brain (20, 46, 47). ¹⁸F-Labeling in a 2,2,2-trifluoroethoxy group instead of an ¹⁸F-fluoroalkyl group could be a strategy to circumvent this issue. This consideration prompted us to investigate the reactivity of ¹¹CF₃CH₂OK with aliphatic substrates. We started with a model compound, a precursor to Posaconazole (®Noxafil) with a tosylate leaving group to optimize precursor amount and reaction temperature (Table S4). ¹¹C-Trifluoroethoxylation produced excellent yields of [¹¹C]45 (89%) under conditions found to be optimal for hypervalent iodonium precursors (Table S4, entry 3). Again, yield did not increase with temperature (Table S4, entry 4). Reduction in precursor amount drastically diminished yield (Table S4, entries 5 and 6). We next tested reaction scope by attempting to prepare a range of ¹¹C-labeled alkyl-2,2,2-trifluoroethyl ethers from aliphatic precursors, including fourteen ¹¹C-labeled biomolecules (Fig. 4). [¹¹C]41 was obtained from a long chain iodoalkyl precursor in acceptable yield (45%). Benzyl halide and α-chloroacetyl precursors were readily converted into their analogous ¹¹C-2,2,2-trifluoroethoxy ethers ([¹¹C]42, [¹¹C]47, [¹¹C]48, [¹¹C]51, [¹¹C]52) in high yields (53–89%) with good tolerance of other functional groups. Aliphatic tosylates derived from a variety of commercially available dug-like molecules (MCPA, Helional, Ketoconazole, Bendazac, an α-D-glucopyranoside derivative, Oxaprozin, Ospemifene, Pterostilbene, and Cyhalofop-butyl) reacted readily with ¹¹CF₃CH₂OK to provide the desired ¹¹C-2,2,2-trifluoroethoxy ethers, [¹¹C]39, [¹¹C]40, [¹¹C]43–[¹¹C]46, [¹¹C]49, [¹¹C]50, and [¹¹C]53–[¹¹C]56, in moderate to excellent yields (34–93%). Precursors with leaving groups attached to an ethylene glycol linker gave excellent yields of ¹¹C-2,2,2-trifluoroethoxy ethers. Notably, aliphatic ¹¹C-trifluoroethoxylation occurred in preference to reaction at aromatic sites.

We measured the molar activity for a model product [¹¹C]1, produced by the ¹¹C-trifluoroethoxylation of 2-chloropyrimidine, to verify that this labeling technique is no-carrier-added (NCA) and gives high molar activity. Starting with about 10 GBq of cyclotron-produced [¹¹C]methane that has been produced from a 10 µA × 10 minute cyclotron irradiation, [¹¹C]1 was obtained with a molar activity of 60 GBq/µmol, corrected to the end of radionuclide production (ERP). Such a high molar activity from a relatively limited cyclotron irradiation shows that the labeling reaction is invulnerable to carrier addition and dilution of molar activity (15, 39).

Having established an efficient route for ¹¹C-trifluoroethoxylation, we next focused on translation of this new labeling method from carbon-11 to fluorine-18 with a few representative substrates. For this purpose, [¹⁸F]fluoroform was produced from no-carrier-added [¹⁸F]fluoride and difluoroiodomethane (48). CF₂¹⁸FCH₂OK was generated by treatment of the [¹⁸F]fluoroform with paraformaldehyde and t-BuOK in DMF in greater than 95% yield. The reactivity of CF₂¹⁸FCH₂OK was assessed under the optimal conditions found for ¹¹C-trifluoroethoxylations (Fig. 5). ¹⁸F-Trifluoroethoxylations of aryl and aliphatic precursors proceeded smoothly and provided corresponding products in moderate to excellent yields similar to those from ¹¹C-trifluoroethoxylation. Heteroarenes, such as pyridine, quinoline, pyrimidine, isothiazole, and 1,3,5-triazine, with halogen leaving groups were converted into the corresponding ¹⁸F-2,2,2-trifluoroethoxy ethers in high yields (82–96%; Fig. 5A). Dependency of labeling position on aryl ring position of the leaving group (e.g., ortho- vs meta- as in [¹⁸F]4 and [¹⁸F]17) or on the nature of the aryl ring (e.g., [¹⁸F]20) was as seen for ¹¹C-labeling. Heteroaryl rings with more structural complexity and diverse functionality were conveniently labeled at room temperature within 5 minutes and produced the corresponding ¹⁸F-labeled compounds in excellent yields ([¹⁸F]15, [¹⁸F]17–[¹⁸F]22; 56–77%; Fig. 5A). These results indicate high potential for application of this labeling method to prospective structurally complex PET tracers. Homoarene precursors, including diaryliodonium salts ([¹⁸F]27 and [¹⁸F]31), aryliodonium ylides ([¹⁸F]35 and [¹⁸F]36), and fluoro precursors ([¹⁸F]37 and [¹⁸F]38), afforded useful yields of ¹⁸F-labeled products (27–69%; Fig. 5B), as for the¹¹C-trifluoroethoxylations. Remarkably, the unprotected hydroxyl group in the Ataluren precursor was well tolerated ([¹⁸F]38) showing compatibility of this labeling protocol to sensitive functionality.

We were keen furthermore to know whether potassium ¹⁸F-2,2,2-trifluoroethoxide could be useful for labeling at aliphatic carbon, given the limited availability of methods for constructing stable alkyl-CF₂¹⁸F bonds (49). In this regard, we tested identical reaction conditions to those used for ¹¹C-trifluoroethoxylation on diverse aliphatic substrates, prepared from drugs, herbicides, and other biomolecules. To our delight, this protocol successfully enabled the installation of a ¹⁸F-2,2,2-trifluoroethoxy moiety onto aliphatic carbon in a variety of complex structures in acceptable to excellent yields ([¹⁸F]44–[¹⁸F]46, [¹⁸F]49–[¹⁸F]56; 15–95%; Fig. 5C). Taken together, these results show that this new methodology, based on the transformation of fluoroform into potassium 2,2,2-trifluoroethoxide and subsequent functionalization of aliphatic carbons, is equally versatile for both carbon-11 and fluorine-18 with the same non-radioactive precursor.

Isotopologues differ only in their isotopic substitutions and play an important role in drug development (50). Deuteration (51) is widely practiced to improve the metabolic stability of PET tracers in ¹⁸F-fluoroalkyl positions. ¹³C-Labeling enables investigations of drug pharmacokinetics and metabolism by ¹³C-NMR spectroscopy and mass spectrometry (52, 53). Simple methods for accessing stable isotopically labeled compounds are highly desirable. The availability of isotopically labeled fluoroforms (H¹²CF₃, H¹¹CF₃, and HCF₂¹⁸F) and paraformaldehyde [(¹²CH₂O)_n, (CD₂O)_n and (¹³CH₂O)_n] and our method for the in situ generation of CF₃CH₂OK from fluoroform, provide an opportunity to explore the incorporation of isotopically labeled 2,2,2-trifluoroethoxy groups into a diverse array of substrates. For demonstration, we synthesized isotopologues of 57, an analog of a well-known COX-1 PET tracer, [¹¹C]PS13 (32). Compounds [¹¹C]57 and [¹⁸F]57 were readily obtained by treating a tosylate precursor with [¹¹C/¹⁸F]CF₃CH₂OK under optimized conditions. The reaction was equally effective when substituting paraformaldehyde with (CD₂O)_n and (¹³CH₂O)_n, leading to high yield syntheses of [²H]57, [²H/¹¹C]57, [²H/¹⁸F]57, [¹³C]57, [¹³C/¹¹C]57, and [¹³C/¹⁸F]57 (Fig. 6). Hence, this novel isotope labeling protocol has exceptional potential for broad application.

Based on an unprecedented transformation of paraformaldehyde with fluoroform, we devised a highly effective one-pot method for appending a wide range of aryl, heteroaryl, and aliphatic organic compounds with an isotopically labeled 2,2,2-trifluoroethoxy group. Especially, reaction of paraformaldehyde with [¹¹C]fluoroform or [¹⁸F]fluoroform efficiently provides ¹¹CF₃CH₂OK and ¹⁸FF₂CH₂OK, respectively, as new, and broadly useful no-carrier-added labeling synthons, with ability to produce novel PET tracers bearing either a ¹¹C- or ¹⁸F-labeled 2,2,2-trifluoroethoxy group. Use of paraformaldehye and fluoroform labeled with stable isotopes (²H, or ¹³C) gives ready access to isotopologues of 2,2,2-trifluoroethoxy compounds. Consequently, the 2,2,2-trifluoroethoxy group may garner increasing interest for both drug and PET tracer development.

General procedure for the one-pot 2,2,2-trifluoroethoxylation of aromatic and aliphatic precursors from fluoroform and isotopically labeled paraformaldehyde

Isotopically labeled (¹²C, ¹³C and ²H) paraformaldehyde (3.0 equiv.) and t-BuOK (3.0 equiv.) were added to a round-bottomed flask equipped with a magnetic stirrer bar followed by DMF (6 mL/1 mmol) under argon atmosphere. A solution of fluoroform (1.0 equiv., 0.3 M) in DMF was added and the reaction mixture was stirred at RT for 3 h. Precursor solution in DMF was added, and the reaction mixture was stirred at RT or 60 ^oC for additional 2 h. The reaction was then quenched with water (2 mL) and the mixture was extracted with DCM (2 × 10 mL). The organic phase was washed with brine, dried (Mg₂SO₄), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give the 2,2,2-trifluoroethyl ether. Purification methods and characterization data of all the individual trifluoroethoxy compounds synthesized in this work can be obtained in the Supplementary Section 1.2, 1.3 and 2.4.

Key labeling intermediates, [ ¹¹ C]Fluoroform and [ ¹⁸ F]fluoroform were synthesized according to literature procedures (22, 48) and the experimental details were provided in Supplementary Section 4.1 and 4.2, respectively.

General procedure for the ¹¹C- and ¹⁸F- 2,2,2-trifluoroethoxylation of aromatic and aliphatic precursors from isotopically labeled fluoroform and paraformaldehyde

About 30 min before the end of radionuclide production, a mixture of t-BuOK (112.2 mg, 1.0 mmol) and paraformaldehyde (15.0 mg, 0.5 mmol) in DMF (6 mL) was prepared in a glovebox under argon and kept there until close to the start of radiochemistry. The t-BuOK-paraformaldehyde reagent mixture in DMF (200 µL) was added to a 1-mL V vial, septum-sealed, removed from the glovebox, and transferred to the lead-shielded hot-cell for the radiochemistry. [¹¹C]Fluoroform or [¹⁸F]fluoroform (37–296 MBq) in DMF (50–300 µL) was added to the vial, mixed, and left at RT for 4 min. A DMF solution (200 µL) of the aromatic or aliphatic precursor (55 µmol) was then added. The reaction mixture was kept at RT for 1 min or heated at 60 ^oC for 3 min and then quenched with water (100 µL). This crude product was analyzed with radio-HPLC as detailed in Supplementary Information. Areas of all the radiochemical product peaks were decay-corrected to the beginning of the HPLC analysis for radiochemical yields calculations. HPLC analysis of each ¹¹C- and ¹⁸F- labeled trifluoroethoxylated products and the respective HPLC chromatograms can be obtained in Supplementary Section 6 and 7.

Acknowledgements

We acknowledge the Intramural Research Program of the National Institutes of Health (NIMH; ZIA-MH002793) for financial support and thank the NIH Clinical Center (Chief Dr. P. Herscovitch) for radioisotope production.

Author contributions

Q.Z., S.T., S.J., C.L.M., contributed to study design and experimental implementation. S.T. and V.W.P. contributed to study design and supervision. All authors contribute to writing and review of the manuscript.

Conflict of interest

There are no conflicts to declare.

Materials and Correspondence

All requests should be addressed to S.T. or V.W.P.

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Isotopologues of Potassium 2,2,2-Trifluoroethoxide for Applications in Positron Emission Tomography and Beyond

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