Radiosynthesis of 18F-labeled reagents for the 18F-difluoromethylation of heteroarenes

The reagent difluoromethyl benzothiazolyl-sulfone (1) has been extensively used in the difluoromethylation of substrates bearing C=C, C≡C, and C≡N bonds by visible light photoredox catalysis. Taking advantage of the reactivity of 1 as difluoromethylating reagent, we intended to perform the radiosynthesis the 18F-labeled compound [18F]1 as a novel labeled compound for late-stage introduction of 18F-difluoromethyl groups. Low activity labeling experiments (150-200 MBq) were performed in order to determine the most suitable conditions for the synthesis of [18F]1. Our results showed that a two-step methodology consisting in the 18F-labeling of the precursor bromofluoromethyl benzothiazolyl-sulfide (4) and subsequent oxidation of the [18F]difluoromethyl benzothiazolyl-sulfide ([18F]2) afforded the cartridge-purified [18F]1 in higher radiochemical yield (RCY). The efficiency of the 18F-labeling reaction was influenced by the following parameters: (i) the type and amount of base and phase-transfer catalyst (PTC) used in the delivery of dry [18F]fluoride ([18F]F-); (ii) the solvent, the temperature, and the reaction time; (iii) the type and amount of 18F-labeling precursor. The amount of the oxidizing agent sodium (meta)periodate (NaIO4) and ruthenium (III) chloride hydrate (RuCl3·xH2O) had a significant impact on the oxidation of [18F]2. Having the optimal conditions in hand, the radiosynthesis of sulfone [18F]1 was fully automated on a GE FASTlabTM synthesizer in conjunction with a semi-preparative high performance liquid chromatography (HPLC) purification procedure. Starting with 120-135 GBq of [18F]fluoride, the sulfone [18F]1 was isolated in 4.5 ± 0.1% RCY [decay-corrected at the start of the synthesis (SOS)] and with a molar activity of 54 ± 7 GBq·μmol-1 at the end of the synthesis (EOS). Following up on the reported efficiency of the [18F]difluoromethyl benzothiazolyl-sulfone ([18F]1) as a 18F-difluoromethylating reagent, we investigated the influence of structurally-related [18F]difluoromethyl heteroaryl-sulfones in the reactivity toward the photoredox C–H 18F-difluoromethylation of heteroarenes under continuous-flow conditions. In the present work, six new [18F]difluoromethyl heteroaryl-sulfones [18F]5a–[18F]5f were prepared and, based on the overall radiochemical yields (RCYs), three of these reagents ([18F]5a, [18F]5c, and [18F]5f) were selected for the fully automated radiosynthesis on a FASTlabTM synthesizer (GE Healthcare) at high level of starting radioactivity. Subsequently, their efficiency as 18F-difluoromethylating reagents was evaluated using the antiherpetic drug acyclovir as a model substrate. Our results showed that the introduction of molecular modifications in the structure of [18F]1 influenced the amount of fac-IrIII(ppy)3 and the residence time needed to ensure a complete C–H 18F-difluoromethylation process. The photocatalytic C–H 18F-difluoromethylation reaction with the reagents [18F]5a, [18F]5c, and [18F]5f was extended to other heteroarenes. Radical-trapping experiments demonstrated the likely involvement of radical species in the C–H 18F-difluoromethylation process.