New Strategies for Transition Metal-mediated Radiofluorination

2 Objectives sition-metal mediated transformations using nucleophilic [18F]fluoride are proving to be powerful reactions for synthesizing previously inaccessible, or difficult to access, radiotracers. For example, our group has previously reported the synthesis of [18F]arenes through the copper-mediated fluorination of (mesityl)(aryl)iodonium salts (Org. Lett., 2014, 16, 3224). While this chemistry is effective for labeling diverse arenes, some users report finding precursor synthesis challenging because of compatibility issues between sensitive functional groups and the oxidizing conditions required to access the hypervalent iodine species. To address this issue, we have a continuing interest in developing strategies for fluorinating a range of readily accessible precursor molecules and qualifying them for the production of clinical radiotracer doses. The objective of this work is to introduce a copped-mediated [18F]fluorination of organostannanes with nucleophilic [18F]fluoride, and expand the scope of our recently reported fluorination of boronic acids and aryl iodides (see Org. Lett., 2015, 17, 5780). The new reactions are being applied to the fluorination of diverse bioactive molecules for both pre-clinical and clinical applications. Methods [18F]Fluoride was produced in a PETTrace cyclotron using the 18O(p, alpha)18F nuclear reaction, trapped on a QMA cartridge and eluted as an aq. solution of a M18F salt (where M = K or Ag). The salt was azeotropically dried and a solution of precursor (ArX where X = SnR3, BX2 or I), copper salt and other additives (see Scheme) were transferred to the reaction vial, heated and then analyzed by radio-TLC and/or -HPLC to determine radiochemical conversion (RCC). Fluorination reactions were either conducted manually or automated using a TRACERLab FXFN synthesis module. Results The use of Cu(OTf)2 and pyridine in conjunction with K18F enabled radiofluorination of aryl stannanes and aryl boronic acids in good yields (X = SnR3, RCC = 12-50%; X = BX2, RCC = 4-73%), while the combination of (tBuCN)2CuOTf2 and Ag18F allowed radiofluorination of aryl iodides in moderate yields (RCC = 2-44%). The methods have been applied to the synthesis of radiotracers of interest to both our clinical (e.g. FPEB, MHPG, DOPA) and preclinical (e.g. 4-[18F]fluorophenacylbromide) imaging programs in similarly good yields (RCC = 8-57%). Conclusions Conclusions: Copper-mediated transformations with nucleophilic [18F]fluoride have enabled fluorination of a range of precursor molecules previously incompatible with nucleophilic fluoride. The chemistry uses mild conditions tolerant of electron-deficient, -neutral or -rich arenes as well as, in many cases, unprotected polar functional groups. Reflecting this, the synthesis methods have enabled the synthesis of radiotracers of interest for both clinical and pre-clinical imaging in our group that would be challenging to prepare using traditional radiofluorination methods. Acknowledgments: financial support from the US DOE (DE-SC0012484 (P.J.H.S.)), NIH (GM073836 (M.S.S.) and T32- EB005172 (P.J.H.S.)), the Alzheimer’s Association (NIRP-14-305669 (P.J.H.S.)) and Merck (M.S.S. and P.J.H.S.) is gratefully acknowledged.