Nucleophilic Substitution of Secondary Tosylates Utilizing [¹⁸F]HF and Iron(III) Acetylacetonate

Objectives: A straightforward method to produce [¹⁸F]HF from fluoride trapped on a quaternary ammonium exchange resin generated via the ¹⁸O(p, n)¹⁸F nuclear reaction was previously reported [1]. In that work, we found that a [¹⁸F]FeF species could be formed and utilized to open epoxides without the need for protecting groups to mask functional groups that are proton donors. The objective of this work was to investigate the ability of this reaction mixture to perform nucleophilic substitution reactions. The utilization of this method could lead to production methods via substitution reaction that do not require masking of proton donors for reaction to occur or the subsequent deprotection steps now required, leading to shorter one pot synthesis of PET imaging agents now requiring multiple steps.

Methods: Fluorine-18 was produced by the ¹⁸O(p, n)¹⁸F nuclear reaction, and trapped on a Waters QMA SepPak Light preconditioned with carbonate (10 mL, 0.5 M K₂CO₃). The fluoride was eluted as [¹⁸F]HF with a solution of TFA in CH₃CN/H₂O 4:1 into a glassy carbon reactor, which had been charged with iron(III) acetylacetonate. The mixture was heated at 80 °C for 10 min to trap [¹⁸F]HF and generate a [¹⁸F]FeF-species that was azeotropically dried at 110 °C. The secondary tosylate dissolved in 1,4-dioxane was added, followed by heating at 120 °C for 20 min. After cooling to 60 °C, HPLC buffer was added and the mixture was removed for analysis by HPLC with UV and radiation detectors.

Results: Secondary tosylates provided product in modest yields with 3[¹⁸F]F-cholestene being generated in a 3.4% non-decay corrected HPLC radiochemical yield and 3[¹⁸F]F-butylbenzene in 1.8% HPLC RCY. When the reaction was attempted with a primary tosylate or bromide no desired product was observed. This is consistent to our observations with epoxides where substituted epoxides performed better.

Conclusions: The conditions resulted in the radiofluorination of secondary toyslates. Further work to optimize the conditions and to investigate how robust the conditions are to substrates containing proton donors is underway. References: [1]Verhoog, S.; Brooks, A.; Mossine, A.; Sanford, M.; Scott, P. J. Nucl. Med. 2018, 59(supplement 1), 1064. Acknowledgements: This work was supported by NIH Grant R01EB021155 from NIBIB and a Michigan Memorial Phoenix Project Seed grant.

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