Synthesis and evaluation of an N-[¹⁸F]fluorodeoxyglycosyl amino acid for PET imaging of tumor metabolism

Introduction: The limitations of [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG), including producing false-positive or -negative results, low image contrast in brain tumor diagnosis and poor differentiation of tumor and inflammatory, necessitate the development of new radiopharmaceuticals. In the present study, a novel [¹⁸F]fluoroglycoconjugate tracer, [¹⁸F]FDGly-NH-Phe, for tumor metabolism imaging was prepared and evaluated.

Methods: [¹⁸F]FDGly-NH-Phe was prepared by condensing [¹⁸F]FDG with L-4-aminophenylalanine in an acidic condition, and purified with semi-preparative-high performance liquid chromatography (HPLC). The in vitro stability study was conducted in phosphate-buffered saline (PBS, pH 4.0-9.18) at room temperature (RT) and in fetal bovine serum (FBS) at 37 °C. The preliminary cellular uptake studies were performed using Hep-2 cell. The bio-distribution studies, PET/CT imaging and metabolism studies were performed and compared with [¹⁸F]FDG on ICR or BALB/c nude model mice.

Results: [¹⁸F]FDGly-NH-Phe was derived from a direct condensation of [¹⁸F]FDG with L-4-aminophenylalanine with high stability in FBS and PBS (pH of 6.5-9.18). In vitro cell experiments showed that [¹⁸F]FDGly-NH-Phe uptake in Hep-2 cells was primarily transported through amino acid transporters including Na⁺-dependent A system, ASC system, and system B^0,+ system. The bio-distribution of [¹⁸F]FDGly-NH-Phe in normal ICR mice showed faster blood radioactivity clearance, and lower uptake in brain and heart than [¹⁸F]FDG. The performance of PET/CT imaging for [¹⁸F]FDGly-NH-Phe in the mice model manifested excellent tumor visualization, high tumor-to-background ratios, and low accumulation in inflammatory lesions. Metabolism studies for [¹⁸F]FDGly-NH-Phe indicated high in vivo stability in plasma and urine and decomposition into [¹⁸F]FDG in the tumor microenvironment.

Conclusion: The results demonstrated that [¹⁸F]FDGly-NH-Phe as a novel amino acid PET tracer showed the capability to differentiate tumor from inflammation, and the potentials for future clinical applications.