Mild syntheses of [^sup 11^C/^sup 18^F]trifluoromethylarenes from [^sup 11^C/^sup 18^F]fluoroform and aryldiazonium salts

Objectives: Trifluoromethylaryl moieties are well represented in established and experimental drugs and PET radiotracers. There is a need for methods for labeling such moieties with the positron-emitters carbon-11 and fluorine-18 in high molar activity. We have recently developed gas-phase methods for producing [11C]fluoroform and [18F]fluoroform [1,2]. Here we tested the reactions of these labeling agents as their copper derivatives with various aryldiazonium tetrafluoroborates (ArN2+BF4-; Ar = 4-MeOC6H4, 4-BrC6H4, 4-NO2C6H4, or 3,5-di-Cl-C6H3) for producing the corresponding labeled trifluoromethylarenes ([11C/18F]ArCF3) (Figure). Methods: [11C]Fluoroform was produced from cyclotron-produced [11C]methane (≤ 30 GBq) by passage in helium over heated (270 °C) CoF3.[1] [18F]Fluoroform was produced in two steps.[2] First [18F]fluoromethane was obtained from cyclotron-produced [18F]fluoride ion (typical molar activity ~ 30 GBq/μmol) by reaction with methyl mesylate in DMSO in the presence of K+-K 2.2.2 at 130 °C for 15 min. The [18F]fluoromethane was then passed over heated (280 °C) CoF3. For labeling reactions, [11C/18F]fluoroform was trapped in cold DMF (~ - 40 °C) and a portion (150-300 μL) converted into [11C/18F]CuCF3 by addition to freshly prepared Cu(t-BuO) (~ 5 μmol)in DMF (50 μL)under dry nitrogen. Et3N.3HF in DMF (1.64% v/v; 50 μL) was then added. Finally, aryldiazonium salt (50 μmol) in DMF (100 μL) was added, mixed thoroughly and left at RT for 10 min. The reaction mixture was quenched with 0.1% TFA water-MeCN (1: 1 v/v), filtered and analyzed with HPLC. The molar activities of [11C/18F]1-methoxy-4-(trifluoromethyl)benzene products were also measured. Results: [11C]Fluoroform and [18F]fluoroform were produced in stable high yields (~ 70% and ~ 97%) from the respective labeled methanes. [11C/18F]Trifluoromethyl arenes were obtained in moderate to high yields (29-39% for 3,5-di-Cl product; 80-98% for 4-substituted products) from the aryldiazonium salts. The molar activities of 11C- and 18F-labeled 1-methoxy-4-(trifluoromethyl)benzene were found to be 145 and 18 GBq/μmol, respectively (corrected to end of radionuclide production). Conclusion: Aryldiazonium salts serve as useful precursors for the radiosynthesis of [11C/18F]trifluoromethylarenes under mild rapid conditions. [11C]Fluoroform gave a high molar activity for [11C]1-methoxy-4-(trifluoromethyl)benzene. [18F]Fluoroform gave a moderate molar activity for [18F]1-methoxy-4-(trifluoromethyl)benzen