Efficient Nucleophilic Radiofluorination of Aryl Chlorides, Aryl Triflates and Nitroarenes with In-Situ NMe418F under Ambient Air

1121 Objectives: We have developed a method for simple and efficient nucleophilic radiofluorination of aryl chlorides, aryl triflates and nitroarenes using in-situ generated tetramethylammonium 18F-fluoride (NMe418F) under ambient air. This method is compatible with a wide range of functional groups and applied to prepare 18F-labeled HQ-415 (a radioligand chelating metal-protein aggregates) for further preclinical PET studies. Methods: [18F]fluoride was produced from 18O-enriched target water via proton beam bombardment in the cyclotron, trapped on a QMA cartridge and eluted as K18F. Once azeotropically dried, a K18F solution was prepared. To a solution of aryl-X (X = Cl, OTf, NO2) with excessive tetramethylammonium salts (NMe4X), a K18F aliquot was added. The reaction vial was heated to form in situ NMe418F and to convert 30 different aryl-X substrates (including 2 bioactive molecules) to aryl-18F products under ambient conditions (Scheme 1). The reaction was showcased in the automated synthesis of 2-18F-quinoline (2-18F-Quin) and the manual synthesis of 18F-HQ415. Activity yield (AY), radiochemical purity (RCY), and molar activity (Am) were determined by Capintec-dose calibrator, radio-TLC, and analytical HPLC, respectively. Results: Nucleophilic radiofluorination of aryl-X (X = Cl, OTf, NO2) with in situ NMe418F generated aryl-18F products in up to 98% TLC RCY (n>3, 30 different aryl-X substrates, Scheme 1). Initial automated synthesis was conducted with 2-Cl-Quin and afforded 2-18F-Quin in 30 ± 3 % automated RCY (n=2) or, by incorporating semi-preparative HPLC purification, 14 ± 2 % isolated decay-corrected AY, and high Am (5.6 ± 1 Ci/µmol) (n=2). Subsequently the method was applied to the manual synthesis of 18F-HQ415. Subjecting Boc-protected Cl-HQ415 precurosr to the optimized radiofluorination conditions, followed by Boc-deprotection with 2M HCl, yielded 18F-HQ415 in 56 ± 3 % (n=3) RCY. Development of an automated synthesis of 18F-HQ415 and qualification of the synthesis for preclinical use is underway. Conclusions: We successfully developed a facile method for efficient nucleophilic radiofluorination of aryl chlorides, aryl triflates and nitroarenes using NMe418F. The NMe418F was easily generated in situ from K18F under ambient air. The method has been applied to a variety of pyridine and quinoline derived substrates including bioactive molecules such as the promising PET radioligand 18F-HQ415. Overall, this operationally simple and reliable process under ambient conditions has high potential for the late-stage radiofluorination of bioactive molecules. Acknowledgements: This work was supported by NIH (R01EB021155) and DOE (DE-SC0012484).