Automated synthesis of [18F]Raltegravir through [18F]fluorobenzylamine

669 Objectives: Raltegravir (Isentress, MK-0518) is the first integrase inhibitor approved by the FDA. It interferes with HIV viral replication when used in combination with antiretroviral therapy. The impetus for this project was to develop an automated synthesis for the preparation of previously labeled [18F]Raltegravir while optimizing the synthesis time, yield, and overall production method [1] to support first-in-human radiopharmacokinetic studies. In order to achieve this, a more robust preparation of [18F]fluorobenzylamine ([18F]FBA) employing improved reduction conditions was developed and microwave coupling reaction conditions needed to be replaced with conventional heating in the Sofie Biosciences ELIXYS FLEX/ CHEM module. Methods: The 4-[18F]fluorobenzylamine ([18F]FBA) chemistry was first automated on the Sofie Biosciences ELIXYS FLEX/ CHEM module. [18F]FBA was synthesized by reacting the 4-N, N, N- trimethylammoniumbenzonitrile triflate with [18F]fluoride ion to form [18F]fluorobenzonitrile. This intermediate was concentrated on a C18 SepPak and then eluted with THF through an in-house formed borohydride exchange reducing resin [2] to yield [18F]FBA that is subsequently trapped on a second C18. THF eluted [18F]FBA was dried in the presence of HCl and the salt was reacted with the Raltegravir precursor with various solvents and bases for various times. Results: The optimized reaction sequence (Figure) has been automated. Facile reduction of the benzonitrile intermediate afforded eluted [18F]FBA (from starting [18F]fluoride ion) in 41 ± 6% yield (n = 15). HCl addition was essential to dry the FBA without substantial evaporative loss. The dried [18F]FBA•HCl was neutralized with DMAP in MeOH and successfully coupled to the Raltegravir precursor at 85 °C for 45 minutes to give the [18F]Raltegravir in 4.61 ± 0.37% yield (n = 2) in a total synthesis time of 135 minutes. Conclusions: Concentrating [18F]FBA with HCl salt also enabled reaction of the complete labeled prosthetic batch as opposed to an aliquot as previously described [2]. The dry down step removes any unreacted [18F]fluorobenzonitrile which is observed in the original synthesis [1] thus leading to a cleaner HPLC chromatogram. This automated process facilitated the successful qualification of [18F]Raltegravir for human imaging studies. Acknowledgements: Funding for this project was granted by Merck. We thank Wenping Li and Michael Klimas for insightful chemistry discussions. References: [1] W. Li, W. Thompson, T. Fisher, J. Wai, D. Hazuda, H. Burns, T. Hamill. J Labelled Comp. Radiopharm. 2009, 53, 517-520 [2] J. Way, F. Wuest . Nucl. Med. Biol. 2013, 40, 430-436