Design, synthesis and evaluation of a novel glutamine derivative (2S,4R)-2-amino-4-cyano-4-[18F]fluorobutanoic acid

Abstract

Glutamine is an important source of nutrients for tumor proliferation. Designing new glutamine-metabolizing PET imaging agents is useful for tumor diagnosis and treatment. Herein, a novel glutamine derivative, (2S,4R)-2-amino-4-cyano-4-[¹⁸F]fluorobutanoic acid, (2S,4R)-4-[¹⁸F]FCABA ([¹⁸F]1), was designed and synthesized. Its absolute configuration was determined by analyzing the single crystal of its derivative. The total synthesis time was 120 min from the end-of-bombardment, and the non-decay-corrected radiochemical yield of [¹⁸F]1 was about 10% (n = 3). In vitro assays of [¹⁸F]1 using MCF-7 cells showed that it utilizes amino acid transporter systems similar to (2S,4R)-4-[¹⁸F]FGln. Biodistribution and small-animal micro-PET imaging showed that [¹⁸F]1 has high tumor-to-muscle ratios at 60 min time point. By using different hydrolysis conditions, the intermediate [¹⁸F]7 can selectively be transformed to [¹⁸F]1, (2S,4R)-4-[¹⁸F]FGln or (2S,4R)-4-[¹⁸F]FGlu.