Radiosynthesis of the anticancer nucleoside analogue Trifluridine using an automated <sup>18</sup>F-trifluoromethylation procedure

King, A. J.; Doepner, Andreas; Turton, David R.; Ciobota, Daniela M.; Pieve, Chiara Da; Fong, Anne-Christine Wong Te; Kramer‐Marek, Gabriela; Chung, Yuen‐Li; Smith, Graham

doi:10.1039/c8ob00432c

Cited by 7 publications

(2 citation statements)

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“…The Cu-difluorocarbene-mediated radiolabelling proceeded with a 6% radiochemical yield and a low molar activity of up to 0.76 GBq/μmol (Scheme 11). King et al developed a method for the labelling of 5-trifluoromethyl-2-deoxyuridine (trifluridine) with fluorine-18 [61]. The difluorocarbene-mediated reaction provided [ 18 F]trifluridine in radiochemical yields of 3% and a molar activity of 0.4 GBq/μmol.…”

Section: Aliphatic [ 18 F]cf 3 Compoundsmentioning

confidence: 99%

Advances in [18F]Trifluoromethylation Chemistry for PET Imaging

Francis

Wuest

2021

Molecules

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Positron emission tomography (PET) is a preclinical and clinical imaging technique extensively used to study and visualize biological and physiological processes in vivo. Fluorine-18 (18F) is the most frequently used positron emitter for PET imaging due to its convenient 109.8 min half-life, high yield production on small biomedical cyclotrons, and well-established radiofluorination chemistry. The presence of fluorine atoms in many drugs opens new possibilities for developing radioligands labelled with fluorine-18. The trifluoromethyl group (CF3) represents a versatile structural motif in medicinal and pharmaceutical chemistry to design and synthesize drug molecules with favourable pharmacological properties. This fact also makes CF3 groups an exciting synthesis target from a PET tracer discovery perspective. Early attempts to synthesize [18F]CF3-containing radiotracers were mainly hampered by low radiochemical yields and additional challenges such as low radiochemical purity and molar activity. However, recent innovations in [18F]trifluoromethylation chemistry have significantly expanded the chemical toolbox to synthesize fluorine-18-labelled radiotracers. This review presents the development of significant [18F]trifluoromethylation chemistry strategies to apply [18F]CF3-containing radiotracers in preclinical and clinical PET imaging studies. The continuous growth of PET as a crucial functional imaging technique in biomedical and clinical research and the increasing number of CF3-containing drugs will be the primary drivers for developing novel [18F]trifluoromethylation chemistry strategies in the future.

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Section: Aliphatic [ 18 F]cf 3 Compoundsmentioning

confidence: 99%

Advances in [18F]Trifluoromethylation Chemistry for PET Imaging

Francis

Wuest

2021

Molecules

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“…15 Among the various fluorinecontaining groups, the trifluoromethyl group (CF 3 ) has received significant attention as its introduction into pharmaceuticals has a major impact on the physical and chemical properties of the molecule such as lipophilicity, pharmacokinetics, and the binding properties of molecules. [16][17][18][19][20] Currently, the late-stage introduction of CF 3 in drug-like compounds is a well-known practice in medicinal chemistry and widely used in the treatment of diseases. 21,22 For example, lansoprazole and omeprazole are popular proton pump inhibitors (PPIs) used as anti-ulcer drugs.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and crystal structure of trifluoromethyl-containing bendamustine hydrochloride

Yin

Liu

Xiao

et al. 2019

Journal of Chemical Research

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A simple strategy to afford trifluoromethyl-containing bendamustine hydrochloride in 34% overall via nine simple steps including substitution, selective reduction, N-acylation, cyclization, esterification, nitro-reduction, N-dihydroxyethylation, chlorination, and acid-catalyzed hydrolysis from commercially available 2,4-dinitrochlorobenzene is described. The structures of the intermediates and target product are established on the basis of infrared, nuclear magnetic resonance, and high resolution mass spectrometer. Moreover, the structure of target product is also confirmed by X-ray crystal analysis, and further studies indicate that the existence of intermolecular O–H···Cl and N–H···Cl hydrogen bonds are effective in stabilization of the crystal structure.

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Synthesis and Derivatization of 1,1‐[¹⁸F]Difluorinated Alkenes

et al. 2018

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A general method for the synthesis of 1,1‐[18F]difluorinated alkenes from [18F]fluoride is reported. This transformation is highly regioselective giving the desired 18F‐fluoroalkenes with radiochemical purities of up to 77 % within 20 minutes and a molar activity (Am) of 1 GBq μmol−1. The transformations are operationally simple to perform and were readily translated onto a commercial automated synthesis unit. The resultant 1,1‐[18F]difluorinated alkene motif is prevalent in numerous drug molecules, and this is the first general method to synthesize this motif with fluorine‐18. 18F‐fluorinated alkenes are excellent building blocks and participate in a number of post‐labeling transformations to access a range of 18F‐perfluorinated functional groups that have never before been radiolabeled with non‐carrier‐added [18F]fluoride. This method considerably expands the range of 18F‐motifs accessible to radiochemists.

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Radiosynthesis of the anticancer nucleoside analogue Trifluridine using an automated ¹⁸F-trifluoromethylation procedure

Abstract: Automated 18F-trifluoromethylation provided the first radiosynthesis of [18F]Trifluridine, which shows potential as a PET probe of drug mechanism of action.

Cited by 7 publications

References 46 publications

Advances in [18F]Trifluoromethylation Chemistry for PET Imaging

Advances in [18F]Trifluoromethylation Chemistry for PET Imaging

Synthesis and crystal structure of trifluoromethyl-containing bendamustine hydrochloride

Synthesis and Derivatization of 1,1‐[¹⁸F]Difluorinated Alkenes

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Radiosynthesis of the anticancer nucleoside analogue Trifluridine using an automated 18F-trifluoromethylation procedure

Abstract: Automated 18F-trifluoromethylation provided the first radiosynthesis of [18F]Trifluridine, which shows potential as a PET probe of drug mechanism of action.

Cited by 7 publications

References 46 publications

Advances in [18F]Trifluoromethylation Chemistry for PET Imaging

Advances in [18F]Trifluoromethylation Chemistry for PET Imaging

Synthesis and crystal structure of trifluoromethyl-containing bendamustine hydrochloride

Synthesis and Derivatization of 1,1‐[18F]Difluorinated Alkenes

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Radiosynthesis of the anticancer nucleoside analogue Trifluridine using an automated ¹⁸F-trifluoromethylation procedure

Synthesis and Derivatization of 1,1‐[¹⁸F]Difluorinated Alkenes