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
