Radiosynthesis of [18F]fluorophenyl-L-amino acids by isotopic exchange on carbonyl-activated precursors

ABSTRACT Aromatic [18F]fluoroamino acids have earlier been developed as promising probes for diagnostics using PET. However, a wider use of these radiofluorinated compounds has been limited due to radiosynthetic constraints. The work here presents an amenable three-step radiosynthesis pathway for the preparation of 2-[18F]fluoro-L-phenylalanine (2-[18F]Fphe), 2-[18F]fluoro-L-tyrosine (2-[18F]Ftyr), 6-[18F]fuoro-L-m-tyrosine (6-[18F]Fmtyr) and 6-[18F]fluoro-L-DOPA (6-[18F]FDOPA). For this, corresponding precursors were 18F-fluorinated by nucleophilic isotopic exchange, followed by either removal of an activating formyl group with Rh(PPh3)3Cl or its conversion by Baeyer-Villiger oxidation, respectively, and subsequent hydrolysis of protecting groups in acidic medium. Two efficient synthetic approaches were developed for the preparation of highly functionalized fluoro-benzaldehydes and -ketones which were used as labeling precursors. The compounds (2S,5S)-tert-butyl 2-tert-butyl-5-(2-fluoro-5-formylbenzyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1a), (2S,5S)-tert-butyl 5-(5-acetyl-2-fluorobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate (1c), (2S,5S)-benzyl 2-tert-butyl-5-(2-fluoro-5-formylbenzyl)-3-methyl-4-oxoimidazolidine-1-carbo-xylate (1d), 4-fluoro-3-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)me-thyl)benzal-dehyde (1e) and 1-(4-fluoro-3-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)me-thyl)phenyl)ethanone (1f), could be prepared in six steps and overall yields of 41%, 48%, 37%, 27%, and 32%, respectively. (2S,5S)-tert-Butyl 5-(4-(benzyloxy)-2-fluoro-5-formylbenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate (1b) was prepared in ten steps with an overall yield of 19% while compounds (2S,5S)-tert-butyl 5-(5-(3,5-bis(trifluoromethyl)-benzoyl)-2-fluorobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate (1g) and (2S,5S)-tert-butyl 2-tert-butyl-5-(2-fluoro-5-(2,2,2-trifluoroacetyl)benzyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1h) were synthesized by a novel three-step procedure in 54% and 40%, respectively. All compounds were obtained with high diasteromeric purity of > 99%. Corresponding precursors 1a, 1d, and 1e were used for the radiosynthesis of 2-[18F]Fphe while 1b was employed for 2-[18F]Ftyr making use of a decarbonylation reaction. The radiosyntheses were performed either under conventional or microwave heating. The conventional heated reactions yielded the desired products 2-[18F]Fphe and 2-[18F]Ftyr in 43% and 49% whereas 34% and 43% RCY, respectively, were obtained when microwave heating was applied. However, 38 min of total preparation time were saved with the latter method, thus providing similar amounts of product activity. The enantiomeric excess achieved for 2-[18F]Fphe was 88% while in the case of 2-[18F]Ftyr 92% was obtained. 6-[18F]Fmtyr was prepared from the Seebach-precursor 1c in 13% overall RCY with a high enantiomeric purity of > 93%. A comparable overall RCY of 11% of 6-[18F]Fmtyr was achieved with the Schöllkopf-precursor 1f while the enantiomeric purity in this case was only 87%. Precursors 1g and 1h showed a relative high RCY of the 18F-for-19F substitution, but a low one in the Baeyer-Villiger oxidation. Thus from 1g and 1h, 6-[18F]Fmtyr was obtained with an overall RCY of only 6% and 13%, respectively. However, the enantiomeric purity of the product using both precursors was > 98%. Based on earlier attempts the nucleophilic radiosynthesis of 6-[18F]FDOPA by isotopic exchange could also be optimized by changing many parameters from the previous work providing ca. 40% RCY and a high enantiomeric purity of > 96%. The specific activity of the tracers prepared here under developmental conditions was as high as that achieved by electrophilic methods. Furthermore, in preliminary studies it could be demonstrated that the automation of the three-step radiochemical synthesis developed here is principally feasible but requires further technical maturation

A three-step radiosynthesis of 6-[ 18 F]fluoro- L-meta -tyrosine starting with [ 18 F]fluoride

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%

Stereoselective radiosynthesis of l- and d-3-[18F]fluoro-α-methyltyrosine

A three-step radiosynthesis is described which allows for the first time the preparation of l- and d-3-[18F]fluoro-α-methyltyrosine starting from [18F]fluoride. Corresponding 3-fluoro-4-formyl-benzylated Schöllkopf derivatives were 18F-fluorinated as precursors by isotopic exchange, followed by Baeyer–Villiger oxidation and subsequent hydrolysis of protecting groups in acidic medium. The three-step, two-pot radiosynthesis provided each enantiomer of 3-[18F]fluoro-α-methyltyrosine with an overall radiochemical yield of 32 ± 8% and an enantiomeric excess ≥95% within 140 min in carrier-added form with a molar activity of 20 GBq/mmol

Baeyer-Villiger oxidation tuned to chemoselective conversion of non-activated [18F]fluorobenzaldehydes to [18F]fluorophenols

A reaction pathway via oxidation of [18F]fluorobenzaldehydes offers a very useful tool for the no‐carrier‐added radiosynthesis of [18F]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 H2SO4 addition, which appears to have a dual effect, acting as catalyst and desiccant. For example, 2‐[18F]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 [18F]fluorophenols rather than [18F]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‐[18F]fluorophenol (RCY 95%; relating to 4‐[18F]fluorobenzaldehyde) and 4‐[18F]fluoro‐m‐tyramine (RCY 32%; relating to [18F]fluoride), respectively