Radiosynthesis ofL-[$^{18}$F]fluorotryptophan by isotopicexchange on carbonyl-activated precursors

In the past a variety of $^{18}$F-labeled aromatic amino acids have been developed, primarily for tumor diagnostics with positron-emission-tomography. Recently tryptophan got high attention, since evidence came up that some tumors exhibit an elevated consumption of it. So far, this amino acid could only be radiofluorinated by unsatisfactory approaches. In the work here, a simpler, 3-step method for a nucleophilic radiosynthesis of L-4-[$^{18}$F]fluorotryptophan was developed. For this a carbonyl activated precursor was radiofluorinated by isotopic exchange, followed by removal of the activating formyl group by reductive decarbonylation and subsequent hydrolysis of the protecting groups under acidic conditions. First, the influence of positions of fluorine and of the formyl group on the isotopic exchange was examined in several fluoro-$\textit{1H}$-indolecarbaldehydes where different protecting groups were attached to the indole nitrogen. Further, a decarbonylation reaction with Rh(PPh$_{3}$)$_{3}$ on those molecules was carried out and optimized. The best results regarding radiochemical yield and chemical stability were obtained with 1-benzyl-4-fluoro-1$\textit{H}$-indole-5-carbaldehyde. Based on these results a concept for the synthesis of precursors for L-6-[$^{18}$F]fluorotryptophan and L-4-[$^{18}$F]fluorotryptophan was developed. Hereby the compounds benzyl (2S,5S)-2-tertbutyl- 5-[(1-benzyl-4-fluoro-5-formyl-1$\textit{H}$–indol–3-yl)methyl]–3–methyl–4–oxoimidazolidine- 1-carboxylate and benzyl (2S,5S)–2–tert–butyl–5-[(1–Boc–4–fluoro–5–formyl-1$\textit{H}$–indol–3 yl) methyl]-3-methyl-4-oxoimidazolidine-1-carboxylate were prepared following 11-step linear synthetic pathways with overall yields of about 8 % and an enantiomeric purity of > 99 %. While the radiosynthesis of L-6-[$^{18}$F]fluorotryptophan was not successful due to the failing hydrolysis of the benzyl group, L-4-[$^{18}$F]fluorotryptophan was prepared by the three step radiosynthesis, consisting of an isotopic exchange, a reductive decarbonylation with Rh(PPh$_{3}$)$_{3}$ and the hydrolysis of the protecting groups with HCl, yielding an enantiomeric purity of > 99 %. After optimization of this procedure L-4-[$^{18}$F]fluorotryptophan was isolated in a radiochemical yield of ca. 13 % and a molar activity of > 70 MBq/mmol within about 115 min. Hence, a new and more efficient nucleophilic radiosynthesis of L-4-[$^{18}$F]fluorotryptophan was developed which is now available for preclinical evaluation