[¹⁸F]Fluorine‐Labeled Pharmaceuticals: Direct Aromatic Fluorination Compared to Multi‐Step Strategies

Abstract

Positron emission tomography (PET) presents an important tool for medicinal and pharmaceutical investigations, with applications ranging from fundamental research to the diagnosis of a broad variety of diseases. Crucial for the use of this technique is, however, a robust labeling strategy for the preparation of the required radiolabeled compound. For 18‐fluorine‐labeling, which represents the most widely applied method in this field, it is interesting to note that a kind of paradigm change occurred over the last years. While multi‐step labeling strategies were the preferred approach for many decades, mainly due to the lack of suitable leaving groups for direct [18F]fluorination reactions, the synthetic tools to achieve the highly attractive direct 18‐fluorine‐labeling rapidly increased recently. This focus review points out a comparison between the multi‐step approaches and the newly developed direct fluorination strategies available for nucleophilic 18‐fluorination of carbocyclic aromatic systems, including a discussion of advantages and limitations.

Radical C–H 18F-Difluoromethylation of Heteroarenes with [18F]Difluoromethyl Heteroaryl-Sulfones by Visible Light Photoredox Catalysis

“…Low starting radioactivity experiments were performed in order to investigate the propensity of the newly synthesized precursors to undergo the expected nucleophilic 18 F-fluorination, under the same 18 F-labeling conditions used to prepare the [ 18 F]difluoromethyl benzothiazolyl-sulfide ([ 18 F]1') [37]. To minimize the radiation exposure, the 18 Precursors 6c (0.02 mmol) and 6a, 6b, 6d-6f (0.04 mmol) in acetonitrile (MeCN, 1 mL) were added to the dry [ 18 F]fluoride and the 18 F-labeling reaction was conducted at 120 °C for 5 min. The crude reaction mixture was pre-purified using a Sep-Pak ® C18 Plus Short cartridge to eliminate the unreacted [ 18 F]fluoride and other polar impurities.…”

“…In addition, PET technology has proven highly valuable in the observation of biochemical and physiological changes that may take place before the anatomical alterations of a certain disease are detected [5][6][7][8]. The suitability of the 18 F radioisotope in anatomical alterations of a certain disease are detected [5][6][7][8]. The suitability of the 18 F radioisotope in PET has encouraged radiochemists to invest much effort in the development of efficient 18 Ffluorination and 18 F-fluoroalkylation strategies [9][10][11][12][13][14][15][16][17][18][19].…”

“…The CF2H substitution may offer a viable alternative to conventional hydrogen-bond donors (e.g., hydroxy (OH) and thiol (SH) groups) in terms of lipophilicity, cell membrane permeability, and metabolic stability, thus modulating the pharmacological activity of pharmaceuticals and agrochemicals [25][26][27][28][29][30][31]. Despite the recent progresses in the preparation of CF2H-containing derivatives in organofluorine chemistry, methodologies for the 18 F-labeling of CF2H groups are still relatively scarce. Most labeling strategies relied on the radiosynthesis of [ 18 F]aryl-CF2H derivatives via 18 F-fluorination of suitable precursors with the electrophilic reagent [ 18 F]Selectfluor bis(triflate) [32] or with the cyclotron-produced [ 18 F]fluoride by aliphatic nucleophilic substitution [33][34][35][36].…”

“…Despite the recent progresses in the preparation of CF2H-containing derivatives in organofluorine chemistry, methodologies for the 18 F-labeling of CF2H groups are still relatively scarce. Most labeling strategies relied on the radiosynthesis of [ 18 F]aryl-CF2H derivatives via 18 F-fluorination of suitable precursors with the electrophilic reagent [ 18 F]Selectfluor bis(triflate) [32] or with the cyclotron-produced [ 18 F]fluoride by aliphatic nucleophilic substitution [33][34][35][36]. Furthermore, the resulting [ 18 F]aryl-CF2H derivatives are afforded in low-to-moderate molar activities (up to 22 GBq·µmol -1 ).…”

Radiosynthesis,in vitroand preliminaryin vivoevaluation of the novel glutamine derived PET tracers [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine

“…However, due to the electrochemical properties of the compound the direct aromatic labelling was not feasible. Direct fluorination of the nitro moiety is possible, but requires harsh labelling conditions30 . In addition, the electrochemical properties are very important for direct aromatic labelling, this can be seen in the dramatic changes of labelling yields of [ 18 F]MPPF depending on the position of the electron withdrawing groups 31 .…”