Late‐Stage ¹⁸F‐Difluoromethyl Labeling of N‐Heteroaromatics with High Molar Activity for PET Imaging

Abstract

Despite ag rowing interest in CHF 2 in medicinal chemistry,there is alackofefficient methods for the insertion of CHF 18 Fi nto druglike compounds.H erein described is ap hotoredoxf lowr eaction for 18 F-difluoromethylation of Nheteroaromatics that are widely used in medicinal chemistry. Following the two-step synthesis for anew 18 F-difluoromethylation reagent, the photoredoxreaction is completed within two minutes and proceeds by CÀHa ctivation, circumventing the need for pre-functionalizationo ft he substrate.T he method is operationally simple and affords straightforwarda ccess to radiolabeled N-heteroaromatics with high molar activity suitable for biological in vivo studies and clinical application.

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

“…We planned the radiosyntheses of the sulfones [ 18 F]5a-[ 18 F]5f following a two-step methodology previously described in the literature [37]. This multi-step strategy involved the initial nucleophilic 18 F-fluorination of the bromofluoromethyl heteroaryl-sulfides 6a-6f and subsequent oxidation of the [ 18 F]difluoromethyl heteroaryl-sulfides [ 18 F]4a-[ 18 F]4f.…”

“…The production of radiotracers with high molar activity is mandatory for PET imaging studies, especially for targeting low-density biomacromolecules. Recently, we disclosed an innovative method reporting the photoredox late-stage C-H 18 F-difluoromethylation of N-containing heteroarenes with the [ 18 F]difluoromethyl benzothiazolyl-sulfone ([ 18 F]1) with improved molar activity [Am ([ 18 F]1) = 54 ± 7 GBq·µmol -1 ] [37,38] ( Figure 1A). In non-radioactive chemistry, difluoromethyl heteroaryl-sulfones have been widely implemented in photoredox catalyzed C-H difluoromethylation processes because of the ability of these compounds to be reduced to CF2H radicals in the presence of appropriate photocatalysts in their photoexcited state.…”

“…In 2019, Liu and co-workers developed a procedure for C-H difluoromethylation of N-arylacrylamides with the reagent difluoromethyl pyridyl-sulfone (2), under visible light photoredox conditions [45] ( Figure 1B). [37,38]. (B) Application of the difluoromethyl sulfones 1 and 2 in the preparation of heterocycles of biological relevance, under visible light photoredox catalysis [39][40][41][42][43][44][45].…”

“…Based on the effectiveness of the sulfone [ 18 F]1 as 18 F-difluoromethylating reagent [37,38], we intended to study the influence of certain molecular modifications in the structure of [ 18 F]1 on the reactivity towards the C-H 18 F-difluoromethylation of N-heteroaromatics. The molecular modifications consisted in the introduction of a single electron-donating (OCH 3 ) ( Figure 2A) or electron-withdrawing (NO 2 ) substituent ( Figure 2B) either at position 5 or 6 of the benzothiazolyl ring and in the alteration of the original benzothiazolyl moiety to other heteroaryl rings (N-methyl-benzimidazolyl and N-phenyl-tetrazolyl rings) ( Figure 2C).…”

“…The molecular modifications consisted in the introduction of a single electron-donating (OCH 3 ) ( Figure 2A) or electron-withdrawing (NO 2 ) substituent ( Figure 2B) either at position 5 or 6 of the benzothiazolyl ring and in the alteration of the original benzothiazolyl moiety to other heteroaryl rings (N-methyl-benzimidazolyl and N-phenyl-tetrazolyl rings) ( Figure 2C). In this work, we opted to perform the radiosyntheses of structurally-related [ 18 F]difluoromethyl heteroaryl-sulfones and subsequently evaluate their efficiency in the photoredox C-H 18 F-difluoromethylation of heteroarenes, under continuous-flow conditions as reported previously [37]. To the best of our knowledge, the effectiveness of the non-radioactive references of these novel [ 18 F]difluoromethyl heteroaryl-sulfones in photoredox C-H difluoromethylation has never been described in the literature.…”