Fluorinated carbohydrates for 18F-positron emission tomography (PET)

Abstract

Carbohydrate diversity is foundational in the molecular literacy that regulates cellular function and communication. Consequently, delineating and leveraging this structure-function interplay continues to be a core research objective in the development of candidates for biomedical diagnostics. A totemic example is the ubiquity of 2-deoxy-2-[¹⁸F]-fluoro-D-glucose (2-[¹⁸F]-FDG) as a radiotracer for positron emission tomography (PET), in which metabolic trapping is harnessed. Building on this clinical success, more complex sugars with unique selectivities are gaining momentum in molecular recognition and personalised medicine: this reflects the opportunities that carbohydrate-specific targeting affords in a broader sense. In this Tutorial Review, key milestones in the development of 2-[¹⁸F]-FDG and related glycan-based radiotracers for PET are described, with their diagnostic functions, to assist in navigating this rapidly expanding field of interdisciplinary research.

Fig. 1. (A) Timeline of key historical milestones in the development of positron emission tomography (PET). (B) Schematic of 2-[¹⁸F]-FDG (1) and its use in various diagnostic fields. (C) Timeline of PET analysis: intravenous injection of a patient with ¹⁸F labelled radiotracer. The radiotracer accumulates in the target cell as it cannot be fully metabolised due to the presence of the C(sp³)–F (metabolic trapping), and subsequently decay to ¹⁸O (through β⁺ decay) is observed. Collision with a positron results in the emission of γ-rays in a 180° angle. The γ-rays are detected by a circular 3D γ-cameras allowing an image to be generated.

Scheme 1. Schematic of d-glucose versus 2-[¹⁸F]-FDG metabolism. Key shows which transport proteins facilitate cellular uptake. [a] Decay of 2-[¹⁸F]-FDG produces d-glucose-6P with a heavy ¹⁸O in the 2-position.

Fig. 2. ¹⁸F-FDG PET/CT fusion image of esophageal squamous cell carcinoma in a 68-years-old woman. The SUV of the tumour was determined to be 3.75 and the metabolic tumour volume was 0.155 m⁻¹. This research was originally published in Radiation Oncology: L. Xia, L., X. Li., J. Zhu, Z. Gao, J. Zhang, G. Yang, Z. Wang, Prognostic value of baseline ¹⁸F-FDG PET/CT in patients with esophageal squamous cell carcinoma treated with definitive (chemo)radiotherapy. Radiat. Onco., 2023, 18, 41. Reused under the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Scheme 2. ¹⁸F Fluorination methods: (upper) electrophilic fluorination produces both 2-[¹⁸F]-FDG (1) and 2-[¹⁸F]-FDM (6) products; (lower) nucleophilic fluorination produces solely glucose-configured 2-[¹⁸F]-FDG (1).

Scheme 3. Enzymatic ¹⁸F fluorination enzyme to produce 5′-[¹⁸F]-FDA. 5′-[¹⁸F]-FDA can be further derivatised with PNP to produce 5′-[¹⁸F]-FDU.

Fig. 3. The relative configuration of selected monosaccharides.

Fig. 4. Structures of selected ¹⁸F monosaccharides.

Scheme 4. The synthesis of [¹⁸F]-FDS (36) by reduction of 2-[¹⁸F]-FDG (1).

Fig. 5. Comparison of [¹⁸F-FDS (36) and ¹⁸F-FDG in BALB/c mice. (a) Red arrow: mice injected with sterile inflammation; Yellow arrow: Aspergillus fumigatus-infected myositis. (b) Green arrow: CT26 tumours. (c) Blue arrow: Staphylococcus aureus-infected myositis. (d) [¹⁸F]-FDS (36) quantification. (e) 2-[¹⁸F]-FDG quantification. This research was originally published in Nature Communications: D. Y. Kim, A. Pyo, S. Ji, S. H. You, S. E. Kim, D. Lim, H. Kim, K. H. Lee, S. J. Oh, Y. Jung, U. J. Kim, S. Jeon, S. Y. Kwon, S. R. Kang, H. B. Lee, H. Hyun, S. Y. Kim, K. S. Moon, S. Lee, S. J. Kang and J. J. Min. In vivo imaging of invasive aspergillosis with ¹⁸F-fluorodeoxysorbitol positron emission tomography, Nat. Commun., 2022, 13, 1–11. Reused under the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Fig. 6. d-Glucose uptake: hydroxyl groups required to enable GLUT or SGLT uptake (left). d-Glucose metabolism: structure activity profile dictating which positions can be modified for tracer design (right).

Fig. 7. Comparison of PET imagers αMe-4-[¹⁸F]-FDG (left) and 2-[¹⁸F]-FDG (right) with MRI (middle) in WHO Grade IV astrocytoma patients. This research was originally published in the Journal of Neuro-oncology: V. Kepe, C. Scafoglio, J. Liu, W. H. Yong, M. Bergsneider, S. C. Huang, J. R. Barrio and E. M. Wright, Positron emission tomography of sodium d-glucose cotransport activity in high grade astrocytomas, J. Neurooncol., 2018, 138, 557–569. Reused under the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Scheme 5. Metabolism of various ¹⁸F radiotracers in comparison to d-glucose (2).

Fig. 8. Structures of disaccharide-based ¹⁸F radiotracers.

Fig. 9. Selected maltodextrin-based ¹⁸F-radiotracers.

Fig. 10. Structures of modified gangliosides GM₁ (upper) and GM₃ (lower).

Scheme 6. (upper) Proposed, reductive mechanism, post-uptake, through passive diffusion. Oxygenated environment: the FMISO radical anion (54) is restored to its original structure through superoxide radical formation. Absence of oxygen: FMISO radical anion (54) is further reduced to amine (56) that can covalently bind macromolecules, resulting in accumulation of FMISO in the cell. (middle) Structures of selected, pentose-based hypoxia radiotracers (57–61). (lower) Structures of selected hexose-based hypoxia radiotracers (62–64).

Fig. 11. Comparison of 2-[¹⁸F]-FDG (1) A and [¹⁸F]-FAZA (57) C on the same CT26 colon carcinoma. B The same CT26 colon carcinoma analyses ex vivo via H&E staining of tumor slices (region shown as red square in A and C). D and E Pimonidazole immunohistochemistry ex vivo. This research was originally published in Radiation Oncology: F. C. Maier, M. Kneilling, G. Reischl, F. Cay, D. Bukala, A. Schmid, M. S. Judenhofer, M. Röcken, H. J. Machulla and B. J. Pichler, Significant impact of different oxygen breathing conditions on noninvasive in vivo tumor-hypoxia imaging using [¹⁸F]-fluoro-azomycinarabino-furanoside ([¹⁸F]FAZA), Radiat. Oncol., 2011, 6, 165. Reused under the Creative Commons Attribution License (https://creativecommons.org/licenses/by/2.0).

Fig. 12. Structures of selected ¹⁸F-modified pyrimidine-based radiotracers.

Fig. 13. Structure of selected adenosine and guanosine tracers (top). Hydrolysis of 5′-[¹⁸F]-FDA (10) to [¹⁸F]-FDR (79) (middle). Structure of selected abasic ribose tracers (bottom).

Emma Campbell

Christina Jordan

Ryan Gilmour