t-Amyl Alcohol Promoted SNAr Radiofluorination of Aryl Halides with [18F]TMAF

147 Objectives: Tetramethylammonium fluoride (TMAF) has been shown to offer unique reactivity in [19F]fluorination reactions when compared to other tetraalkylammonium fluorides (e.g. TBAF). One explanation for this enhanced reactivity is the inability of this reagent to undergo deleterious Hofmann Elimination.(1) We have previously demonstrated that in-situ generated [18F]TMAF is effective for the SNAr radiolabeling of aromatic precursors of low reactivity, such as 2-chloroarenes.(2) In this presentation, we disclose that pre-generated [18F]TMAF is also an effective reagent for SNAr fluorine-18 labeling of these precursors. Notably, replacement of MeCN during fluoride azeotropic drying with 2-methyl-2-butanol (t-AmylOH) improves the reaction efficiency. Methods: Fluorine-18 was produced in a cyclotron via the 18O(p, n)18F nuclear reaction and trapped on a Waters QMA SepPak Light preconditioned with 0.5M NaHCO3 and eluted with aqueous tetramethylammonium salt or K2CO3 into a TracerLab FXFN radiosynthesis module reactor and dried with MeCN or t-AmylOH before redissolution in DMSO. For manual reactions (n≥2 runs), [18F]TMAF was removed from the reactor and transferred to 1-dram vials containing the remaining reactants including 100 µmol chloroarene. The reaction was heated to 100 or 180 oC for 30 min before analysis via radio-TLC and radio-HPLC. For automated reactions, 100 µmol substrate in DMSO was delivered directly into the reactor and stirred at 100 oC for 30 min before analysis via radio-TLC and radio-HPLC. Results: Initial attempts to label 2-chloroquinoline with in-situ generated [18F]TMAF from [18F]KF + tetramethylammonium salts gave modest (<15%) radiochemical conversions (RCC), and the addition of various aliphatic alcohols did not improve reaction efficiency. In contrast, switching to pre-generated [18F]TMAF by eluting with a TMA salt from the QMA followed by azeotropic drying with t­-AmylOH led to significantly higher RCCs for labeled azine and benzenoid products, including 89±5% for [18F]2-fluoroquinoline (n=2). Notably, the radiosynthesis of this compound was successfully automated in 44% RCY using a standard dry down procedure with MeCN. Switching the dry down solvent to t-AmylOH improved the RCY to 55%. As a control, the use of a corresponding TBA salt under an analogous protocol did not produce any detectable radiolabeling product, and these experiments indicate an enhancement in reaction efficiency mediated by t-AmylOH in conjunction with [18F]TMAF.(3) Conclusions: We present SNAr radiolabeling using pre-generated [18F]TMAF promoted by t-AmylOH. The newly developed protocol offers an alternative to previously described in-situ­ preparations and is amenable to the radiofluorination of (hetero)aromatic chlorides in good to excellent RCCs and RCYs. Further studies are currently underway to understand the effect of tetramethylammonium counterions introduced during the elution stage. Acknowledgements: This work was supported by NIH (R01EB021155). References: [1] Schimler SD, Ryan SJ, Bland DC, Anderson JE, Sanford MS. Anhydrous Tetramethylammonium Fluoride for Room-Temperature S N Ar Fluorination. J Org Chem. 2015;80:12137-12145.[2] Lee SJ, Brooks AF, Morales Colon M, Makaravage K, Sanford MS, Scott PJ. Efficient Nucleophilic Radiofluorination of Aryl Chlorides, Aryl Triflates and Nitroarenes with In-Situ NMe418F Under Ambient Air. In: Journal of Nuclear Medicine; 2020:S1-1121.[3] Kim DW, Ahn D-S, Oh Y-H, Lee S, Kil HH, Oh SJ, Lee SJ, Kim JS, Ryu JS, Moon DH, Chi DY. A New Class of SN2 Reactions Catalyzed by Protic Solvents: Facile Fluorination for Isotopic Labeling of Diagnostic Molecules. J Am Chem Soc. 2006;128:16394-16397.