Synthesis of optically pure 4-fluoro-L-glutamines as potential tumor imaging agents

Objectives Recently, glutamine (Gln) was suggested as an alternative source of nutrient for tumor growth. Such tumors may not be detected by FDG. Therefore, Gln and its analogs are potentially useful as metabolic indicators for studying increased utilization of Gln in tumors. The synthesis of stereospecific fluorine-18 labeled 4-fluoro-L-glutamines (4-FGln) is reported herein as potential, tumor-imaging agents.

Methods The Passerini three-component reaction, de-acetylation, tosylation and TASF fluorination reactions were processed for assembling the carbon-4 position being functionalized Gln. Radio-synthesis was initiated by submitting tosylated Gln intermediates to the standard nucleophilic substitution reaction, followed by the TFA deprotection process, which was performed in order to prepare F-18 labeled 4-FGln. In vitro tumor cell (9L.C6) uptake and inhibition studies were conducted.

Results A new synthetic pathway to fluorinated Gln derivatives was developed. The synthesis of two optically pure 4-FGlns, 4-fluoro-(2S, 4S)-glutamine and 4-fluoro-(2S, 4R)-glutamine, was accomplished using a Passerini three-component reaction and TASF nucleophilic fluorination reaction as key steps. In addition, two tosylated Gln derivatives, which are suitable precursors for fluorination reaction, were synthesized on a multi-gram scale. Furthermore, preparation of F-18 substituted Glns was successfully performed. In vitro cell uptake studies (9L.C6 tumor cells) show that the uptake of these radiotracers is highly specific and it is likely associated with the up-regulation of Gln transporters in tumor cells.

Conclusions The results suggest that these fluorine-labeled Gln analogs may be potential useful as tumor metabolic imaging agents, especially for those tumors that may lack of FDG uptake