Abstract
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Objectives Radiolabeling of non-activated aromatics is not easily achieved by nucleophilic aromatic fluorination. The goal of this study was to develop a one-step and regiospecific 18F-fluorination method for (hetero)aromatics bearing electron-rich and/or sterically hindered substituents under metal-free conditions using spiro hypervalent iodine(III)-based precursors.
Methods Azeotropically dried [18F]Et4NF (3 mCi) was resolubilized in DMF (400 μL), followed by addition of the respective spiroiodine(III) precursor (2 mg). The reaction was carried out at 120 °C for 10 min. Fluorine incorporation and product identities were determined by radioTLC and HPLC (n≥3). Fifteen substrates with diverse chemical scaffolds (18F-building blocks and radiotracers) were successfully labeled and key compounds were isolated.
Results Using 4-[18F]fluorobiphenyl as a testing platform, eleven iodine(III) auxiliaries were explored as precursors. A spiroiodine(III) precursor (stable solid) afforded the highest incorporation yield (85±3%). With this spiro auxiliary, various non-activated aromatics (15 examples) were labeled in high yields. Representative examples include 2-[18F]fluoro-1,3,5-triisopropylbenzene (56%), 4-bromo-1-[18F]fluoro-2-methoxybenzene (56%), 1-[18F]fluoro-6-methyl-3-nitrobenzene (32%), 3-[18F]fluoro N-acetylaniline (17%), 6-[18F]fluoroindoline (34%), and 6-[18F]fluorophenyl alanine (55%). 4-[18F]Fluorobenzyl azide, a useful reagent for click chemistry, was synthesized in one-step and isolated with 28±8% uncorrected radiochemical yield and specific activity >100 mCi/μmol relative to only 3 mCi of starting [18F]fluoride in 45 min.
Conclusions Spiroiodine(III) based precursors offer a one-step and regiospecific methodology to radiolabel non-activated and sterically hindered aromatic compounds with [18F]fluoride. Fifteen substrates were efficiently radiolabeled including the building block 4-[18F]fluorobenzyl azide. Applications of this technology to prepare new radiopharmaceuticals will be presented.