Nucleophilic [¹⁸F]Fluorination and subsequent decarbonylation of methoxy‐substituted nitro‐ and halogen‐benzenes activated by one or two formyl groups

Abstract

As model reactions for the introduction of 18 F into protected aromatic amino acids, the replacement of NO 2 , Cl, Br and F by [ 18 F]fluoride in 2-isophthalaldehyde and 2-terephthalaldehyde derivatives which model 18 F-DOPA and 18 F-tyrosine was investigated by comparing labelling yields and reaction rates with those of corresponding mono-aldehyde compounds. All isophthalaldehydes showed maximum radiochemical yields (79 to 86%) at 1401C and in comparison with the corresponding mono-aldehydes the reaction proceeded faster. At lower temperature the reaction already resulted in high yields, e.g. 2-nitroisophthalaldehyde was labelled with a yield of 78% at 251C after 7 min, whereas 2-nitrobenzaldehyde only reached a yield of 1.7% under the same reaction conditions. The 18 F/NO 2 exchange in nitroterephthalaldehydes proceeded more slowly and with lower radiochemical yields when compared with corresponding isophthalaldehydes and monoaldehydes.

6-[18F]Fluoro-L-DOPA: A Well-Established Neurotracer with Expanding Application Spectrum and Strongly Improved Radiosyntheses

“…By optimization of the amounts of reagents during the alkylation process, they were able to obtain [ 18 F]F-DOPA in RCYs of 20 ± 4%, SAs of ~50 GBq/ μ mol, and ee of ≥95% within 120 min synthesis time. In order to obtain higher RCYs, it is important to radiolabel the nitro precursor 15 in DMF instead of DMSO due to oxidation processes of the aldehyde 15 occurring in DMSO [ 84 , 85 ]. Furthermore, the utilization of HBr in combination with KI in the deprotection step resulted in higher RCYs compared to HI alone.…”

Syntheses of meta‐[18F]fluorobenzaldehyde and meta‐[18F]fluorobenzylbromide from phenyl(3‐Formylphenyl) iodonium salt precursors

“…Sometimes, meta‐ [ 18 F]fluorobenzaldehyde is needed in order to prepare radiopharmaceuticals with an exact molecular structure of interest and current yields obtained for meta‐ [ 18 F]fluorobenzaldehyde from meta‐ nitrobenzaldehyde are very low25–27 because the meta ‐position of benzaldehyde is comparatively electron rich. Nucleophilic [ 18 F]F − radiolabeling of such non‐activated aromatic rings can be carried out by introducing an activating group with its removal or modification after labeling 28, 29. Diaryliodonium salts represent a particularly interesting approach, since they have been shown to be useful precursors for direct nucleophilic [ 18 F]F − introduction into both electron‐rich and electron‐deficient aromatic rings 30–37.…”

Synthesis and Preliminary Evaluations of a Triazole-Cored Antagonist as a PET Imaging Probe ([18F]N2B-0518) for GluN2B Subunit in the Brain

“…However, 18 F-labeled compound 11 ([ 18 F] 11 ) was obtained in poor radiochemistry yield (RCY) < 3% (decay corrected) and difficult to purify by high-performance liquid chromatography (HPLC) because of overlapping impurities. The low RCY of this method may be caused by the lack of an appropriate leaving group in 17 , i.e., an electron-withdrawing group at its ortho or para position. , As our alternative strategy, we explored a stepwise synthesis of [ 18 F] 11 and [ 18 F] 13 using SCIDY method , (Scheme B). The corresponding precursors 20 and 21 were prepared from the oxidation of iodinated azidobenzenes ( 18 and 19 , the synthesis is shown in Scheme S1, Supporting Information) with mCPBA, followed by ligand exchange with SPIAd in the same overall yields of 36%.…”

“…The low RCY of this method may be caused by the lack of an appropriate leaving group in 17, i.e., an electronwithdrawing group at its ortho or para position. 55,56 As our alternative strategy, we explored a stepwise synthesis of [ 18 F] 11 and [ 18 F]13 using SCIDY method 43,44 ). Furthermore, since the 1,2,3-triazole linker shows good biostability in vivo and is used as an isosteric surrogate for peptide bond, 57 our radiolabeling method may provide a highly efficient modular synthesis route for the preparation of new 18 F-arene click agents.…”