[18F]FBQ-C2 as a metabolically stable glutamine derivative for cancer imaging

Objectives: Glutamine is the most abundant amino acid in the blood and free amino acid pool. Same with glycolysis, glutaminolysis was found that it plays a vital role in the metabolic network of tumor cells as energy, building block, and signaling molecule. Tumor cells would like to increase the Gln uptake to generate more energy for survival, even including some “glycolysis / FDG-negative” tumor. To imaging glutaminolysis in tumors, 18F-(2S,4R)4-Fluoroglutamine ([18F]FGln) and fluoroboronoglutamine ([18F]BF3-Gln) were developed and used in tumor imaging successfully. But both of them lack enough stability and bring significant bone uptake and non-specific uptake. In this study, [18F]FBQ-C2, as a stable Gln PET tracer, with two more carbon in the side chain of [18F]BF3-Gln, was developed and investigated.

Methods: [18F]FBQ-C2 was radiolabeled through 18F-19F isotope exchange and purified by Al2O3 Column. The stability in vitro was studied by radio-TLC. Competitive inhibition in BGC823 cell was conducted to study the transporter specificity. In vivo small-animal [18F]FBQ-C2 PET imaging and Biodistribution was conducted in healthy BGC823-xenografts-bearing Nu/Nu mice, which was compared with [18F]BF3-Gln and [18F]FGln.

Results: [18F]FBQ-C2 was synthesized in high 35% RCY and over 98% radiochemical purity. [18F]FBQ-C2 shown extreme stability in vitro and no defluorination was observed in 2 hours 37℃ PBS. The competitive inhibition implied that [18F]FBQ-C2 enter cells via ASCT2 specifically, which is the same with natural glutamine. PET study and Biodistribution probed that [18F]FBQ-C2 is stable in vivo with low bone uptake (0.81±0.20%ID/g) and can be cleaned rapidly in most tissues. Dynamic scan in mice bearing BGC823 xenografts and pharmacokinetics study implied that [18F]FBQ-C2 was accumulated in tumor specifically with the longer half-life (101.18±6.50min) than other tissues (52.70±12.44min in muscle). PET study in mice bearing BGC823 xenografts shown that [18F]FBQ-C2 can bring high-contrast tumor imaging with low background. Biodistribution displays high tumor to normal tissues ratio (4.8±1.7 in tumors, 2.5±1.0 in stomachs, 2.2±0.9 in livers and 17.8±8.4 in brains).

Conclusions: [18F]FBQ-C2 is a stable PET tracer for Gln imaging in tumors. It can perform high-contrast tumor imaging, which was promising to be a potential PET tracer in clinical research.

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