18F-Fluorination Using Tri-Tert-Butanol Ammonium Iodide as Phase-Transfer Catalyst: An Alternative Minimalist Approach

Abstract

The 18F syntheses of tracers for positron emission tomography (PET) typically require several steps, including extraction of [18F]fluoride from H2[18O]O, elution, and drying, prior to nucleophilic substitution reaction, being a laborious and time-consuming process. The elution of [18F]fluoride is commonly achieved by phase transfer catalysts (PTC) in aqueous solution, which makes azeotropic drying indispensable. The ideal PTC is characterized by a slightly basic nature, its capacity to elute [18F]fluoride with anhydrous solvents, and its efficient complex formation with [18F]fluoride during subsequent labeling. Herein, we developed tri-(tert-butanol)-methylammonium iodide (TBMA-I), a quaternary ammonium salt serving as the PTC for 18F-fluorination reactions. The favorable elution efficiency of [18F]fluoride using TBMA-I was demonstrated with aprotic and protic solvents, maintaining high 18F-recoveries of 96–99%. 18F-labeling reactions using TBMA-I as PTC were studied with aliphatic 1,3-ditosylpropane and aryl pinacol boronate esters as precursors, providing 18F-labeled products in moderate-to-high radiochemical yields. TBMA-I revealed adequate properties for application to 18F-fluorination reactions and could be used for elution of [18F]fluoride with MeOH, omitting an additional base and azeotropic drying prior to 18F-labeling. We speculate that the tert-alcohol functionality of TBMA-I promotes intermolecular hydrogen bonding, which enhances the elution efficiency and stability of [18F]fluoride during nucleophilic 18F-fluorination.

Nucleophilic Radiofluorination Using Tri-tert-Butanol Ammonium as a Bifunctional Organocatalyst: Mechanism and Energetics

“…Scheme 1 presents the structure of TBMA-I, which is transformed to TBMA- 18 F by Shinde and co-workers’ procedure [ 13 ], along with the 18 F-fluorination of the model substrate 1,3-ditosylpropane 1 . Carrying out the reaction in CH 3 CN selectively produced the 18 F-labeled product [ 18 F]2 with an RCY of 20% in CH 3 CN ( Table 1 ).…”

“…The 18 F-fluorination [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ] of organic compounds is gaining considerable importance for synthesizing chemicals that can be employed as radiotracers for the diagnosis of various diseases [ 21 , 22 , 23 ] by the highly sensitive imaging technique of positron emission tomography (PET) [ 24 , 25 ]. Electrophilic substitution reactions [ 26 , 27 , 28 ] using the carrier added [ 18 F]F 2 gas were the earlier method for this purpose, but this approach usually suffers from poor radiochemical yields (RCYs) and from the difficulty of handling the [ 18 F]F 2 gas.…”

“…Various non-radioactive nucleophilic fluorination methods [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ] have been developed using various phase-transfer catalysts (PTCs) for their application in radiopharmaceutical chemistry in which hydrogen bonding between protic PTC and nucleophile [ 18 F]fluoride enhances the reaction and selectivity [ 36 , 37 ]. The recent development of tri-( tert -butanol)-methylammonium [ 18 F]fluoride (TBMA- 18 F) [ 13 ] as a promoter for radiofluorination demonstrated an excellent [ 18 F]fluoride elution efficiency under the reduced basicity of [ 18 F]fluoride, with moderate to good obtained RCYs. This technique seems to allow a single-step reaction scheme for the synthesis of 18 F-labeled substances, which would be a significant advance.…”

Ionic Liquids as Organocatalysts for Nucleophilic Fluorination: Concepts and Perspectives

“…Use of ILs for synthesizing 18 F-labeled radiophamaceutical substances also looks promising. Although not an IL, the recently reported reaction of 18 F-fluorination by a tert -butanol-integrated quaternary ammonium salt (tri-( tert -butanol)-methylammonium fluoride [ 83 , 84 ] shows this possibility.…”

A closer look at the synthesis of 2-[18F]fluoroethyl tosylate to minimize the formation of volatile side-products

“…There are no reports in the literature, so far, addressing the mechanism by which [ 18 F] FEOH is formed during [ 18 F]FEtOTs "conventional" radiosynthesis using the K 2 CO 3 / K 222 system in dry acetonitrile. Still, Shinde et al, (Shinde et al 2021) showed that the synthesis of [ 18 F]fluoropropyl tosylate using 1,3-ditosylpropane as precursor and a base/ precursor molar ratio of 1 in dry conditions, generated a side-product (29% yield) that was identified as [ 18 F]fluoropropanol. Furthermore, the same synthesis was performed using tetraethyl ammonium bicarbonate (TEAB) and tri-(tert-butanol)-methylammonium iodide (TBMA-I) as phase transfer catalysts, with 60% RCY of [ 18 F]fluoropropyl tosylate and 7% of [ 18 F]-fluoropropanol for TEAB; and 21% RCY of [ 18 F]fluoropropyl tosylate with no formation of [ 18 F]fluoropropanol when using TBMA-I.…”