18F‐Labeled aromatic amino acids exhibit great potential for diagnostic applications using positron emission tomography. However, the introduction of 18F into aromatic compounds remains challenging, and novel fluorination methods facilitating easy access to 18F‐labeled arenes are highly sought after. In recent years, novel metal‐mediated fluorination methods have been reported and transferred into radiochemistry. Based on Cu‐mediated radiofluorination, a two‐step synthesis of no‐carrier‐added (n.c.a.) 6‐[18F]fluoro‐l‐tryptophan was developed. 6‐[18F]Fluoro‐l‐tryptophan was synthesized with an overall radochemical yield of 16 ± 4% within 110 min and a specific activity of 280 GBq µmol–1. The radiochemical purity was more than 99 %. The developed method allowed access to radiofluorinated tryptophan derivatives in high radiochemical yields and opens new ways to provide radiofluorinated amino acids. Furthermore, the reaction conditions were optimized to facilitate automation.

2-[(18)F]Fluoro-L-phenylalanine and 2-[(18)F]fluoro-L-tyrosine have been developed as promising radiopharmaceuticals for molecular imaging using positron emission tomography (PET). However, the lack of a convenient radiosynthetic pathway has limited their practical use. In this work a new three-step nucleophilic synthesis of these compounds starting from [(18)F]fluoride is described. Corresponding precursors (1a and 1b) were (18)F-fluorinated by isotopic exchange, followed by the removal of an activating formyl group with Rh(PPh(3))(3)Cl and subsequent hydrolysis of protecting groups in acidic medium. All reactions were carried out using both conventional and microwave heating. Conventional heated reactions yielded the desired products 2-[(18)F]Fphe and 2-[(18)F]Ftyr in 43% and 49% whereas radiochemical yields of 34% and 43%, respectively, were obtained when they were heated by microwaves. Under optimized conditions the enantiomeric purity was ≥94% for both radiopharmaceuticals.

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The radiosynthesis of 6-[(18)  F]fluoro-L-m-tyrosine has generally been performed by electrophilic radiofluorination, which exhibits several drawbacks. In the present work, a three-step radiochemical synthesis is described starting from [(18)  F]fluoride. The synthetic sequence, including isotopic exchange, Baeyer-Villiger oxidation, and hydrolysis, were examined comparing four fluorobenzophenone derivatives as labeling precursors. Of those, (2S,5S)-tert-butyl 5-(5-acetyl-2-fluorobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate (1a) and (2S,5S)-tert-butyl 2-tert-butyl-5-(2-fluoro-5-(2,2,2-trifluoroacetyl)benzyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1d) proved to be the most suitable ones. 6-[(18)  F]Fluoro-L-m-tyrosine was obtained with overall radiochemical yields of 8-13% and an enantiomeric excess of up to 98%.

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A reaction pathway via oxidation of [ 18 F]fluorobenzaldehydes offers a very useful tool for the no-carrier-added radiosynthesis of [ 18 F]fluorophenols, a structural motive of several potential radiopharmaceuticals. A considerably improved chemoselectivity of the Baeyer-Villiger oxidation (BVO) towards phenols was achieved, employing 2,2,2-trifluoroethanol as reaction solvent in combination with Oxone or m-CPBA as oxidation agent. The studies showed the necessity of H 2 SO 4 addition, which appears to have a dual effect, acting as catalyst and desiccant. For example, 2-[ 18 F]fluorophenol was obtained with a RCY of 97% under optimised conditions of 80°C and 30-minute reaction time.The changed performance of the BVO, which is in agreement with known reaction mechanisms via Criegee intermediates, provided the best results with regard to radiochemical yield (RCY) and chemoselectivity, i.e. formation of [ 18 F]fluorophenols rather than [ 18 F]fluorobenzoic acids. Thus, after a long history of the BVO, the new modification now allows an almost specific formation of phenols, even from electron-deficient benzaldehydes. Further, the applicability of the tuned, chemoselective BVO to the n.c.a. level and to more complex compounds was demonstrated for the products n.c.a. 4-[ 18 F]fluorophenol (RCY 95%; relating to 4-[ 18 F]fluorobenzaldehyde) and 4-[ 18 F]fluoro-m-tyramine (RCY 32%; relating to [ 18 F]fluoride), respectively.