Evaluating <i>N</i>‐difluoromethyltriazolium triflate as a precursor for the synthesis of high molar activity [<sup>18</sup>F]fluoroform

Pees, Anna; Vosjan, Maria J. W. D.; Chai, Jin Young; Cha, Hyojin; Yoon, Dae; Windhorst, Albert D.; Vugts, Daniëlle J.

doi:10.1002/jlcr.3939

“…However, this exchange barrier is reduced in the presence of added Lewis acids [5f–k] . A number of groups have reported on access to copper [ 18 F]trifluoromethyl reagents that can transfer a radiolabeled CF 3 group to aryl and heteroaryl hosts [5m–s] . These reactions commonly require [ 18 F]fluoroform gas, however, one‐pot reactions that allow the direct use of [ 18 F]fluoride have been developed [5m,n] .…”

Section: Figurementioning

confidence: 99%

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

Khanapur

¹

,

Lye

²

,

Mandal

³

et al. 2022

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We report a general method for the labeling of both CF 3 and CF 2 H groups in a broad range of chemical settings (aryl, oxide, sulfide). The method utilizes frustrated Lewis pair mediated selective CÀ F activation to formally substitute fluorine-19 with fluorine-18 in a two-step defluorination/radiofluorination process, and as such can utilize the target compounds as starting materials. The radiotracer precursors can be isolated as stable salts prior to radiofluorination. The method delivers good radiochemical yields and molar activities (up to 35.2 � 6.5 % non-decay corrected isolated activity yields and 12.0 � 1.7 GBq μmol À 1 molar activities) and is shown to be applicable to biologically relevant compounds. The ability to utilize the target compound as the starting material and the synthetic simplicity of the method coupled with the ever-increasing use of CF 3 and CF 2 H groups in pharmaceuticals makes this method attractive for drug and radiotracer development.In molecular imaging, fluorine-18 (t 1/2 � 110 min) finds use as the most suitable radionuclide for positron-emission tomography (PET). [1] PET utilizes radiotracers that contain (most commonly) the positron-emitting fluorine-18 to noninvasively image biological tissue and organs in real-time. Most notably, PET is utilized in diagnostic medicine but has also found application in pharmacokinetic studies. [2] Recent attention has turned to the incorporation of fluorine-18 into difluoromethyl and trifluoromethyl groups due to their increasing presence in bioactive molecules as bioisosteres. [3] The ability to readily label CF 3 and CF 2 H groups with fluorine-18 in biologically relevant molecules for use in PET would directly benefit drug development, pharmacokinetic studies and biological imaging. [4] A number of reports have demonstrated incorporation of fluorine-18 into CF 2 H and CF 3 (Figure 1, A). [5] For example, halogen exchange (Halex) has been utilized to generate fluorine-18 labeled CF 2 H and CF 3 groups, most successfully with bromide leaving groups. [5a-k] The harsh reaction conditions required for exchange of CÀ X bonds

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“…However, this exchange barrier is reduced in the presence of added Lewis acids [5f–k] . A number of groups have reported on access to copper [ 18 F]trifluoromethyl reagents that can transfer a radiolabeled CF 3 group to aryl and heteroaryl hosts [5m–s] . These reactions commonly require [ 18 F]fluoroform gas, however, one‐pot reactions that allow the direct use of [ 18 F]fluoride have been developed [5m,n] .…”

Section: Figurementioning

confidence: 99%

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

Khanapur

¹

,

Lye

²

,

Mandal

³

et al. 2022

Angewandte Chemie

1

0

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We report a general method for the labeling of both CF 3 and CF 2 H groups in a broad range of chemical settings (aryl, oxide, sulfide). The method utilizes frustrated Lewis pair mediated selective CÀ F activation to formally substitute fluorine-19 with fluorine-18 in a two-step defluorination/radiofluorination process, and as such can utilize the target compounds as starting materials. The radiotracer precursors can be isolated as stable salts prior to radiofluorination. The method delivers good radiochemical yields and molar activities (up to 35.2 � 6.5 % non-decay corrected isolated activity yields and 12.0 � 1.7 GBq μmol À 1 molar activities) and is shown to be applicable to biologically relevant compounds. The ability to utilize the target compound as the starting material and the synthetic simplicity of the method coupled with the ever-increasing use of CF 3 and CF 2 H groups in pharmaceuticals makes this method attractive for drug and radiotracer development.In molecular imaging, fluorine-18 (t 1/2 � 110 min) finds use as the most suitable radionuclide for positron-emission tomography (PET). [1] PET utilizes radiotracers that contain (most commonly) the positron-emitting fluorine-18 to noninvasively image biological tissue and organs in real-time. Most notably, PET is utilized in diagnostic medicine but has also found application in pharmacokinetic studies. [2] Recent attention has turned to the incorporation of fluorine-18 into difluoromethyl and trifluoromethyl groups due to their increasing presence in bioactive molecules as bioisosteres. [3] The ability to readily label CF 3 and CF 2 H groups with fluorine-18 in biologically relevant molecules for use in PET would directly benefit drug development, pharmacokinetic studies and biological imaging. [4] A number of reports have demonstrated incorporation of fluorine-18 into CF 2 H and CF 3 (Figure 1, A). [5] For example, halogen exchange (Halex) has been utilized to generate fluorine-18 labeled CF 2 H and CF 3 groups, most successfully with bromide leaving groups. [5a-k] The harsh reaction conditions required for exchange of CÀ X bonds

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“…Exceptionally, Pees et al [14h] . have recently produced [ 18 F]fluoroform with a very usefully high molar activity of 153 GBq/ μ mol by treating N ‐difluoromethyltriazolium triflate with [ 18 F]fluoride.…”

Section: Introductionmentioning

confidence: 99%

“…Several methods have been devised to produce [ 18 F]fluoroform, [14a–h] the majority in solution with gas phase isolation [14a,d–h] and some in situ for direct use [14b,c] . [ 18 F]Fluoroform is readily converted by copper(I) bromide in DMF solution into its more reactive copper(I) derivative [14c–e] and has been used for the conversion of aryl halides, [14b–f] aryl boronic acids, [14d–f] aryldiazonium salts, [14f,15] and aryl stannanes, [16] into [ 18 F]trifluoromethylarenes (Scheme 1, Equation 2).…”

Section: Introductionmentioning

confidence: 99%

Broad‐scope Syntheses of [¹¹C/¹⁸F]Trifluoromethylarenes from Aryl(mesityl)iodonium Salts

Telu

¹

,

Jana

²

,

Haskali

³

et al. 2023

Chemistry A European J

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Efficient methods for labeling aryl trifluoromethyl groups to provide novel radiotracers for use in biomedical research with positron emission tomography (PET) are keenly sought. We report a broad‐scope method for labeling trifluoromethylarenes with either carbon‐11 (t1/2=20.4 min) or fluorine‐18 (t1/2=109.8 min) from readily accessible aryl(mesityl)iodonium salts. In this method, the aryl(mesityl)iodonium salt is treated rapidly with no‐carrier‐added [11C]CuCF3 or [18F]CuCF3. The mesityl group acts as a spectator allowing radiolabeled trifluoromethylarenes to be obtained with very high chemoselectivity. Radiochemical yields from aryl(mesityl)iodonium salts bearing either electron‐donating or electron‐withdrawing groups at meta‐ or para‐ position are good to excellent (67–96 %). Ortho‐substituted and otherwise sterically hindered trifluoromethylarenes still give good yields (15–34 %). Substituted heteroaryl(mesityl)iodonium salts are also viable substrates. The broad scope of this method was further exemplified by labeling a previously inaccessible target, [11C]p‐trifluoromethylphenyl boronic acid, as a potentially useful labeling synthon. In addition, fluoxetine, leflunomide, and 3‐trifluoromethyl‐4‐aminopyridine, as examples of small drug‐like molecules and candidate PET radioligands, were successfully labeled in high yields (69–81 %).

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Evaluating N‐difluoromethyltriazolium triflate as a precursor for the synthesis of high molar activity [¹⁸F]fluoroform

Cited by 7 publications

References 18 publications

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

Broad‐scope Syntheses of [¹¹C/¹⁸F]Trifluoromethylarenes from Aryl(mesityl)iodonium Salts

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Evaluating N‐difluoromethyltriazolium triflate as a precursor for the synthesis of high molar activity [18F]fluoroform

Cited by 7 publications

References 18 publications

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

Broad‐scope Syntheses of [11C/18F]Trifluoromethylarenes from Aryl(mesityl)iodonium Salts

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Evaluating N‐difluoromethyltriazolium triflate as a precursor for the synthesis of high molar activity [¹⁸F]fluoroform

Broad‐scope Syntheses of [¹¹C/¹⁸F]Trifluoromethylarenes from Aryl(mesityl)iodonium Salts