Background: After the discovery of 2-fluoro-2-deoxyglucose (FDG)^[1] and its [¹⁸F]-derivative,^[2] it has been widely used in PET/CT imaging due to the higher metabolism of carbohydrates in malignant cells. This led to the investigation of other carbohydrates and their possible application as nuclear imaging agents according to their own unique metabolic pathways. A redesigned radiofluorinated fructose analogue, 4-fluoro-4-deoxyfructose ([¹⁸F]4-FDF), was developed to trap the phosphorylated metabolite by considering aldolase’s catalytic mechanism. The C₄-fluorination prevented aldolase-mediated scission, resulting in cellular trapping of 4-FDF.^[3] To follow up on 4-FDF, the C₄-stereoisomer [¹⁸F4-fluoro-deoxytagatose ([¹⁸F]4-FDT) was synthesized^[4] and its PET imaging performance compared to [¹⁸F]4-FDF. Results and discussion: [¹⁸F]4-FDT exhibited comparable radiochemical yield and molar activity as [¹⁸F]4-FDF. Both tracers were subjected to PET/CT imaging, performed on an Si78 PET/CT scanner with a 4-position hotel having adjustable isoflurane and respiratory monitoring for each position. Tail veins were catheterized, and an anatomic CT scan was acquired over the whole of the mouse bodies. The study included four fed and four fasted female BALB/c mice each. [¹⁸F]4-FDT shows significantly higher bone uptake than its C₄-stereoisomer (Fig. 1A). Tagatose is metabolized similarly to fructose, converted to the 1-phosphate by fructokinase then is cleaved by aldolase, but at half the rate.^[5] Here the i.v. administration of [¹⁸F]4-FDT led to markedly different biodistribution than [¹⁸F]4-FDF. Additionally, the effect of dietary status (i.e. fed vs. fasted) had a significant impact on [¹⁸F]4-FDT uptake in the heart, brain and liver, which was not observed for [¹⁸F]4-FDF (Figure 1B). The metabolism of isotopically labelled [U¹³C]4-FDT will be followed in vitro by mass spectrometry. Conclusion: While [¹⁸F]4-FDF is a successful imaging biomarker for fructolysis in high-glycolytic index tissues and is going into clinical trial, [¹⁸F]4-FDT is an interesting example of a small stereochemical change with a contrary outcome, shedding more light on tagatose metabolism.

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Image/Figure Caption:

A) Comparative PET/CT imaging of ([¹⁸F]4-FDT) and [¹⁸F]4-FDF in fed and fasted female BALB/c mice. B) Comparison of time–activity areas under curve for brain, heart, and liver.

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