Addressing Chirality in the Structure and Synthesis of [¹⁸ F]5-Fluoroaminosuberic Acid ([¹⁸ F]FASu)

An increasing number of positron emission tomography (PET) radiotracers are being developed that are modelled on various amino acids to better understand disease in a manner that is complementary to traditional glycolysis-targeting [¹⁸ F]-fluorodeoxyglucose. Since chiral centers are ubiquitous in amino acids, generating an optically pure radiolabeled amino acid is important for patient dose, image quality and understanding the physiology behaviour. Past studies on the radiosynthesis of amino acid radiotracers seldom address the impact of reaction conditions on their chirality. The amino acid PET tracer, [¹⁸ F]5-fluoroaminosuberic acid ([¹⁸ F]FASu), has two chiral centers at the 2- and 5-positions and is being developed as a specific tracer for the cystine transporter (system x_C^- ), a biomarker for oxidative stress. Herein we report a method for synthesizing pure 2S,5R/S-FASu. We have resolved the 5-position configuration by applying Mosher's method combined with 2D NMR, which has enabled the synthesis of ¹⁸ FASu with fully known configuration. Our study serves as an example of a systematic method to identify and characterize amino acid tracers with chiral centers.