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1 The described photocatalytic 18F-difluoromethylation protocol involving the newly synthesized reagents can suitable for the development of novel [18F]CF2H-containing radiotracers for PET imaging with improved molar activities. + 1555 word(s) 1555 2020-04-15 12:27:23 |
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Lemos, A.L.P.; Trump, L.; Lallemand, B.; Pasau, P.; Mercier, J.; Lemaire, C.; Monbaliu, J.; Genicot, C.; Luxen, A. [18F]Difluoromethyl Heteroaryl-Sulfones. Encyclopedia. Available online: (accessed on 19 June 2024).
Lemos ALP, Trump L, Lallemand B, Pasau P, Mercier J, Lemaire C, et al. [18F]Difluoromethyl Heteroaryl-Sulfones. Encyclopedia. Available at: Accessed June 19, 2024.
Lemos, Agostinho Luís Pereira, Laura Trump, Bénédicte Lallemand, Patrick Pasau, Joël Mercier, Christian Lemaire, Jean-Christophe Monbaliu, Christophe Genicot, André Luxen. "[18F]Difluoromethyl Heteroaryl-Sulfones" Encyclopedia, (accessed June 19, 2024).
Lemos, A.L.P., Trump, L., Lallemand, B., Pasau, P., Mercier, J., Lemaire, C., Monbaliu, J., Genicot, C., & Luxen, A. (2020, April 25). [18F]Difluoromethyl Heteroaryl-Sulfones. In Encyclopedia.
Lemos, Agostinho Luís Pereira, et al. "[18F]Difluoromethyl Heteroaryl-Sulfones." Encyclopedia. Web. 25 April, 2020.
[18F]Difluoromethyl Heteroaryl-Sulfones

The suitability of the 18F radioisotope in positron emission tomography (PET) demanded novel approaches for 18F-fluorination and 18F-fluoroalkylation. The difluoromethyl (CF2H) group has gained increasing attention in medicinal chemistry due to its lipophilic hydrogen-bond donor properties. In non-radioactive chemistry, difluoromethyl heteroaryl-sulfones has been extensively used in difluoromethylation of substrates bearing C=C, C≡C, and C≡N bonds by visible light photoredox catalysis. Herein, we highlight our recent work on the synthesis of [18F]difluoromethyl heteroaryl-sulfones with improved molar activities and their application in photoinduced C-H 18F-difluoromethylation of N-containing heteroarenes via a radical-mediated pathway.

fluorine-18 difluoromethylation heteroarenes visible light photocatalysis

1. Introduction

The fluorine-18 radioisotope has been regarded the "radionuclide of choice" for in vivo positron emission tomography (PET) imaging in living subjects since it provides a unique combination of nuclear and physical features over alternative short-lived positron emitters such as carbon-11, nitrogen-13, and oxygen-15[1][2][3][4]. Fluorine-18 has a high positron yield resulting from an almost exclusive β+ emission (97%) with this mode of decay producing the stable oxygen-18 isotope. The half-life of 109.8 min allows sufficient time for multistep synthetic labeling reactions and the transport of 18F-labeled radiotracers over considerable distances. Furthermore, the relatively low positron energy of fluorine-18 (0.635 MeV) is highly advantageous in the acquisition of high-resolution PET images[1][2][3][4]. The distinctive sensitivity of PET makes this technique suitable for the study of absorption, distribution, metabolism, and excretion (ADME) properties of radiopharmaceuticals and the evaluation of their pharmacodynamic profile. In addition, PET technology has proven highly valuable in the observation of biochemical and physiological changes that may take place before the anatomical alterations of a certain disease are detected[5][6][7][8]. The suitability of the 18F radioisotope in PET has encouraged radiochemists to invest much effort in the development of efficient 18F-fluorination and 18F-fluoroalkylation reactions[9][10][11]

Among the existing fluorinated motifs, the difluoromethyl (CF2H) group has received considerable attention in medicinal chemistry due to its lipophilic hydrogen-bond donor properties. The CF2H substitution may offer a viable alternative to conventional hydrogen-bond donors [e.g., hydroxy (OH) and thiol (SH) groups] in terms of lipophilicity, cell membrane permeability, and metabolic stability, thus modulating the pharmacological activity of pharmaceuticals and agrochemicals[12][13]. Thus, the synthesis of radiotracers with 18F-difluoromethyl groups has been recently explored due to the attractive characteristics of fluorine-18 and CF2H motifs in radiopharmaceutical chemistry. 

2. Overview of the different strategies for the synthesis of [18F]aryl-CF2H derivatives

Despite the recent progresses in the preparation of CF2H-containing derivatives in organofluorine chemistry[14][15][16], methodologies for the 18F-labeling of CF2H groups are still relatively scarce and mainly relied on the radiosynthesis of [18F]aryl–CF2H derivatives via 18F-fluorination reactions (Figure 1). In 2013, Gouverneur and co-workers disclosed a silver(I)-mediated protocol enabling the 18F-fluorodecarboxylation of 2-fluoro-2-arylacetic acids with [18F]Selectfluor bis(triflate), an electrophilic 18F-fluorinating reagent[17] (Scheme 1A). The cyclotron-produced [18F]fluoride was employed for the first time to access [18F]aryl–CF2H derivatives by AgOTf-mediated 18F-fluorination of aryl-CHFCl precursors[18] (Scheme 1B). In 2016, Ritter developed an alternative approach for the construction of [18F]aryl–CF2H functionalities starting from aryl (pseudo)halides via activation of a benzoyl auxiliary followed by benzylic bromination and in situ halogen exchange with [18F]fluoride[19] (Scheme 1C). Later, Liang and co-workers described an alternative approach for the preparation of [18F]aryl–CF2H with improved molar activity[20]. This synthetic approach consisted in the initial nucleophilic 18F-fluorination of benzyl (pseudo)halides and subsequent oxidative benzylic C-H fluorination with Selectfluor under transition metal-free conditions (Scheme 1D). In 2019, Gouverneur reported the utilization of aryl boronic acids as substrates to afford [18F]aryl-CF2H through copper-mediated cross-coupling with ethyl bromofluoroacetate and manganese-mediated 18F-fluorodecarboxylation with [18F]tetraethylammonium fluoride ([18F]TEAF) and iodosobenzene (PhIO)[21] (Scheme 1E). 

Scheme 1. Methods for the radiosynthesis of [18F]aryl-CF2H derivatives. (A) Silver(I)-mediated 18F-fluorodecarboxylation of 2-fluoro-2-arylacetic acids with [18F]Selectfluor bis(triflate)[17](B) Silver(I)-mediated 18F-labeling of aryl-CHFCl precursors with [18F]KF[18]. (C) Palladium-catalyzed fluoroacetophenonation of aryl (pseudo)halides and subsequent 18F-labeling of aryl acetophenones[19]. (D) Nucleophilic 18F-fluorination of benzyl (pseudo)halides and oxidative benzylic C-H fluorination[20](E) Manganese-mediated 18F-fluorodecarboxylation of 2-fluoro-2-arylacetic acids with [18F]TEAF[21]

These methods allowed the radiosynthesis of [18F]aryl–CF2H derivatives with low-to-moderate molar activities (up to 22 GBq·μmol-1). The production of radiotracers with high molar activity is mandatory for PET imaging studies, especially for targetting low-density biomacromolecules. Obtaining a high molar activity still constitutes a major challenge in the preparation of [18F]CF2H–bearing compounds, due to the unwanted 18F–19F isotopic exchange reactions.

3. Radiosynthesis of [18F]difluoromethyl heteroaryl-sulfones for C-H 18F-difluoromethylation of heteroarenes by visible light photoredox catalysis

In 2019, our laboratories described an innovative and efficient protocol enabling the late-stage introduction of 18F-difluoromethyl moieties in N-containing heteroarenes with the [18F]difluoromethyl benzothiazolyl-sulfone ([18F]1) with improved molar activity [Am ([18F]1) = 54 ± 7 GBq·μmol-1][22][23] (Figure 1A). In non-radioactive chemistry, difluoromethyl heteroaryl-sulfones have been extensively employed in photoredox-catalyzed difluoromethylation of substrates bearing C=C, C≡C, and C≡N bonds because of the ability of these compounds to be reduced to CF2H radicals in the presence of appropriate photocatalysts in their photoexcited state. In 2016, Hu and Fu reported the use of difluoromethyl benzothiazolyl-sulfone (1) in the radical difluoromethylation of biphenyl isocyanides[24] and olefinic amides[25], respectively. The reagent 1 was also employed in the preparation of CF2H–substituted heterocycles of biological relevance, including isoquinolinediones[26], coumarins[27], isoxazolines[28], and oxindoles[29]. In 2019, Liu and co-workers developed a procedure for the difluoromethylation of N-arylacrylamides with the reagent difluoromethyl pyridyl-sulfone (2), under visible light photoredox conditions[30] (Figure 1B).

Figure 1. (A) Photoredox C–H 18F-difluoromethylation of N-containing heteroarenes with [18F]difluoromethyl benzothiazolyl-sulfone ([18F]1), under continuous-flow conditions[22][23]. (B) Application of the difluoromethyl sulfones 1 and 2 in the preparation of heterocycles of biological relevance, under visible light photoredox catalysis[24][25][26][27][28][29][30].

Taking advantage of the reported efficiency of the [18F]1 as 18F-difluoromethylating reagent[22][23], our laboratories planned to study the influence of certain molecular modifications in the structure of [18F]1 in the reactivity toward the photoredox C-H 18F-difluoromethylation of heteroarenes, under continuous-flow conditions[31]. The molecular modifications consisted in the single introduction of an electron-donating (EDG) or an electron-withdrawing group (EWG) either at position 5 or 6 of the benzothiazolyl ring and the modification of the original benzothiazolyl moiety to other heteroaryl rings (N-methyl-benzimidazolyl and N-phenyl-tetrazolyl rings). Six structurally-related [18F]difluoromethyl heteroaryl-sulfones ([18F]5a-[18F]5f) were synthesized on a GE FASTlabTM synthesizer via a two-step sequence (Scheme 2). The nucleophilic 18F-fluorination of bromofluoromethyl heteroaryl-sulfides (3a-3f) was carried out in the presence of potassium carbonate (K2CO3) and Kryptofix® 222 (K2.2.2), and afforded the cartridge-purified [18F]difluoromethyl heteroaryl-sulfides ([18F]4a-[18F]4f) in 8.3–14.8% RCYs [decay-corrected at the start-of-synthesis (SOS)]. After optimization of the oxidation step with sodium (meta)periodate (NaIO4) and ruthenium (III) chloride hydrate (RuCl3·xH2O), the sulfones [18F]5a-[18F]5f were afforded in 70.6–91.9% RCYs (decay-corrected at the SOS). 

Scheme 2. Two-step radiosynthesis of [18F]difluoromethyl sulfones bearing electron-rich ([18F]5a and [18F]5b) and electron-poor benzothiazolyl groups ([18F]5c and [18F]5d) and other heteroaryl rings ([18F]5e and [18F]5f). All radiochemical yields (RCYs) are of the cartridge-purified products and decay-corrected at the SOS. 

Based on the RCYs of the two-step radiosyntheses of the cartridge-purified [18F]5a[18F]5f, the electron-rich benzothiazolyl derivative [18F]5a, the electron-poor benzothiazolyl derivative [18F]5c, and the N-phenyl tetrazolyl derivative [18F]5f were selected for the investigation of their reactivity toward 18F-difluoromethylation of N-containing heteroarenes. In order to circumvent any potential radioprotection issues, the radiosyntheses of the three 18F-labeled compounds were fully automated on a FASTlabTM synthesizer (GE Healthcare) in conjunction with an additional high performance liquid chromatography (HPLC) purification. The fully automated radiosyntheses of [18F]5a, [18F]5c, and [18F]5f (18F-labeling, oxidation, HPLC purification, and formulation) were performed in 73 min, 70 min, and 65 min, respectively. Starting from 125-150 GBq of [18F]fluoride, the [18F]5a, [18F]5c, and [18F]5f were isolated in 2.9 ± 0.1%, 5.7 ± 0.5%, and 8.0 ± 0.9% RCYs (decay-corrected at the SOS), respectively. Improved molar activities at the end of the synthesis (EOS) were achieved under these radiolabeling conditions [Am ([18F]5a) = 139 ± 17 GBq·μmol−1 > Am ([18F]5f) = 113 ± 17 GBq·μmol−1 > Am ([18F]5c) = 62 ± 12 GBq·μmol−1 > Am ([18F]1) = 54 ± 7 GBq·μmol−1] (Table 1). 

 Table 1. Radiochemical yields and molar activities of [18F]5a, [18F]5c, and [18F]5f.

[18F]Difluoromethyl Heteroaryl-Sulfones [18F]5a [18F]5c [18F]5f
Duration of the radiosynthesis (min) 73 70 65
RCY (%) 2.9 ± 0.1 5.7 ± 0.5 8.0 ± 0.9
Molar activity (GBq·μmol-1) 139 ± 17 62 ± 12 113 ± 17

Subsequently, the efficiency of [18F]5a, [18F]5c, and [18F]5f as 18F-difluoromethylating reagents was evaluated using the antiherpetic drug acyclovir as a model substrate. The 18F-difluoromethylation reactions were carried out under continuous-flow conditions, in the presence of the photocatalyst fac-IrIII(ppy)3. Our results demonstrated that the introduction of molecular modifications in the structure of [18F]1 can modulate the reactivity of the resulting 18F-difluoromethylating reagents, influencing the amount of fac-IrIII(ppy)and the residence time needed to ensure a complete C-H 18F-difluoromethylation reaction. The photocatalytic 18F-difluoromethylation protocol with the reagents [18F]5a, [18F]5c, and [18F]5f was extended to other heteroarenes (Scheme 3; [18F]5a: 17-57% RCYs; [18F]5c: 13-66% RCYs; [18F]5f: 14-60% RCYs). Radical-trapping experiments demonstrated the likely involvement of radical species in the 18F-difluoromethylation process.

Scheme 3. Scope of [18F]heteroaryl-CF2H derivatives. All RCYs were determined based on the radio-TLC and radio-UPLC purities of the crude products. 


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