Synthesis and Biological Evaluation of Fluorine-18 and Deuterium Labeled l-Fluoroalanines as Positron Emission Tomography Imaging Agents for Cancer Detection

Abstract

To fully explore the potential of ¹⁸F-labeled l-fluoroalanine for imaging cancer and other chronic diseases, a simple and mild radiosynthesis method has been established to produce optically pure l-3-[¹⁸F]fluoroalanine (l-[¹⁸F]FAla), using a serine-derivatized, five-membered-ring sulfamidate as the radiofluorination precursor. A deuterated analogue, l-3-[¹⁸F]fluoroalanine-d₃ (l-[¹⁸F]FAla-d₃), was also prepared to improve metabolic stability. Both l-[¹⁸F]FAla and l-[¹⁸F]FAla-d₃ were rapidly taken up by 9L/lacZ, MIA PaCa-2, and U87MG cells and were shown to be substrates for the alanine-serine-cysteine (ASC) amino acid transporter. The ability of l-[¹⁸F]FAla, l-[¹⁸F]FAla-d₃, and the d-enantiomer, d-[¹⁸F]FAla-d₃, to image tumors was evaluated in U87MG tumor-bearing mice. Despite the significant bone uptake was observed for both l-[¹⁸F]FAla and l-[¹⁸F]FAla-d₃, the latter had enhanced tumor uptake compared to l-[¹⁸F]FAla, and d-[¹⁸F]FAla-d₃ was not specifically taken up by the tumors. The enhanced tumor uptake of l-[¹⁸F]FAla-d₃ compared with its nondeuterated counterpart, l-[¹⁸F]FAla, warranted the further biological investigation of this radiotracer as a potential cancer imaging agent.