Simple and rapid radiosynthesis of N-18F-labeled glutamic acid as a hepatocellular carcinoma PET tracer

Abstract

Introduction: We have reported that N-(2-¹⁸F-fluoropropionyl)-L-glutamate (¹⁸F-FPGLU) showed good tumor-to-background contrast and ¹⁸F-FPGLU was prepared via complex multi-step reaction sequence; here, it is synthesized by a facile two-step reaction sequence. The objectives of this study are to synthesize ¹⁸F-FPGLU via a two-step reaction sequence and to evaluate the value of ¹⁸F-FPGLU in nude mice bearing human hepatocellular carcinoma SMCC-7721 (HCC SMCC-7721).

Methods: ¹⁸F-FPGLU was synthetized from the precursor (2S)-dimethyl 2-(2-bromopropanamido)pentanedioate via the two-step on-column hydrolysis using a modified commercial FDG synthesizer. To investigate the transport mechanism of ¹⁸F-FPGLU, we conducted a series of competitive inhibition experiments on HCC SMCC-7721 cells in the absence or presence of Na⁺ and various types of inhibitors. Small-animal PET-CT imaging was performed on tumor-bearing nude mice using ¹⁸F-FPGLU and 2-¹⁸F-2-deoxy-D-glucose (¹⁸F-FDG).

Results: The radiochemical yield of ¹⁸F-FPGLU was up to 15±5% (EOS, n=10) in 35min with the two-step procedure and the radiochemical purity was higher than 95% with a specific activity of 30-40GBq/μmol. In vitro cell experiments show that ¹⁸F-FPGLU is primarily transported through the Na⁺-dependent system X_AG- and Na⁺-independent system X_C-. PET imaging in a tumor model indicates that ¹⁸F-FPGLU may be superior to ¹⁸F-FDG for hepatocellular carcinoma (HCC) imaging.

Conclusion: An optimized route to prepare ¹⁸F-FPGLU was developed and ¹⁸F-FPGLU was synthetized from the precursor ((2S)-dimethyl 2-(2-bromopropanamido)pentanedioate) via the two-step on-column hydrolysis. ¹⁸F-FPGLU was a potential novel PET tracer for HCC imaging.

Keywords: Amino acid transport; Hepatocellular carcinoma; N-(2-(18)F-fluoropropionyl)-L-glutamate; Positron emission tomography (PET).