Radiosyntheses using fluorine-18: the art and science of late stage fluorination

Abstract

Positron (β(+)) emission tomography (PET) is a powerful, noninvasive tool for the in vivo, three-dimensional imaging of physiological structures and biochemical pathways. The continued growth of PET imaging relies on a corresponding increase in access to radiopharmaceuticals (biologically active molecules labeled with short-lived radionuclides such as fluorine-18). This unique need to incorporate the short-lived fluorine-18 atom (t1/2 = 109.77 min) as late in the synthetic pathway as possible has made development of methodologies that enable rapid and efficient late stage fluorination an area of research within its own right. In this review we describe strategies for radiolabeling with fluorine-18, including classical fluorine-18 radiochemistry and emerging techniques for late stage fluorination reactions, as well as labeling technologies such as microfluidics and solid-phase radiochemistry. The utility of fluorine-18 labeled radiopharmaceuticals is showcased through recent applications of PET imaging in the healthcare, personalized medicine and drug discovery settings.

Figure 1

PET imaging detector. Positron emission followed by an annihilation event and detection of photons.

Figure 2

Differentiation of Dementia Subtypes using PET Imaging (adapted from Burke, J. F. et al. Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography, Brain, 2011, 134 (Pt. 6), 1647-57; by permission of Oxford University Press)

Figure 3

(a) [¹⁸F]SPA-RQ; (b) Positron emission tomography (PET) image from the striatum of a subject who received aprepitant 100 mg. Predose (top) and postdose (bottom). Subject number 01, estimated occupancy = 94%; (c) estimated relationship between plasma concentration of aprepitant and occupancy of striatal NK₁ receptors. Curve depicted is based on fit of the data to the Hill equation (slope = 1) ((b) and (c) reprinted from M. Bergström et al., Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant, Biol. Psychiatry, 2004, 55, 1007-1012, Copyright (2004), with permission from Elsevier).

Figure 4

Typical patterns of ¹⁸F-flutemetamol uptake in negative scan (left) and positive scan (right). White matter uptake is similar in both scans, but there is considerably more uptake in gray matter in the positive scan (this research was originally published in JNM: R. Lundqvist et al. Implementation and Validation of an Adaptive Template Registration Method for ¹⁸F-Flutemetamol Imaging Data. J. Nucl. Med. 2013, 54, 1472-1478. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Scheme 1

Synthesis of [¹⁸F]FDG: (a) electrophilic fluorination of 3,4,6-tri-O-acetyl-D-glucal 1 by [¹⁸F]F₂, (b) electrophilic fluorination of 3,4,6-trihydroxy-D-glucal 2 with [¹⁸F]acetyl hypofluorite, and (c) nucleophilic aliphatic substation of 1,3,4,6-tetra-O-acetyl-2-O-triflate-β-D-mannose 3.

Scheme 2

Synthesis (a) and synthetic applications (b,c,d) of [¹⁸F]N-fluorobenzenesulfonamide.

Scheme 3

Synthesis (a) of [¹⁸F]N-fluoro-N-alkylsulfonamide [¹⁸F]4, and subsequent applications (b,c).

Scheme 4

Synthesis of (a) [¹⁸F]N-fluoropyridone [¹⁸F]5, and (b,c) reactions.

Scheme 5

Synthesis (a,b) of [¹⁸F]Selectfluor bis(triflate) ([¹⁸F]7), (c,d) and synthetic applications.

Scheme 6

(a) [¹⁸F]Fluoride-derived palladium (IV) electrophilic fluorinating reagent [¹⁸F]4. (b) Palladium (II) aryl complex reaction with [¹⁸F]9. (c) Fluorine-18 radiopharmaceuticals.

Scheme 7. Nickel-mediated oxidative fluorination with aqueous [¹⁸F]fluoride

Scheme 8. Synthesis of (a) 5-[¹⁸F]fluorouracil 15 and (b) 4-[¹⁸F]fluoroantipyrine 17

Scheme 9

2-[¹⁸F]fluorotyrosine and 3-[¹⁸F]fluorotyrosine synthesis is highly reagent dependent.

Scheme 10

6-[¹⁸F]fluoroDOPA ([¹⁸F]FDOPA) synthesis by (a) unselective direct fluorination and (b) selective fluorination via organometallic precursors. *RCY and SA given for deprotected [¹⁸F]FDOPA.

Scheme 11

Electrophilic fluorination of aryl Grignard and aryl lithium compounds via carbanion intermediates.

Scheme 12. Radiosynthesis of [¹⁸F]FEOBV and [¹⁸F]AMYViD™

Scheme 13. Strategies for the Synthesis of [¹⁸F]FLT

Scheme 14

Pd-Catalyzed allylic [¹⁸F]fluorination reactions.

Scheme 15. Radiosynthesis of [¹⁸F]MPPF

Scheme 16. Radiosynthesis of [¹⁸F]Flutemetamol

Scheme 17. Synthesis of Radiolabeled Phenols via Bayer-Villiger Chemistry

Scheme 18

Diaryliodonium salts for the preparation of [¹⁸F]fluoroarenes.

Scheme 19

[¹⁸F]Fluoroarenes from triarylsulfonium salts.

Scheme 20

p-[¹⁸F]Fluoroarenes from diarylsulfoxides.

Scheme 21. Radiosynthesis of NAChR Radioligands (a) [¹⁸F]2-FA and (b) [¹⁸F]Flubatine

Scheme 22. Radiosynthesis of (a) [¹⁸F]FCH and (b) [¹⁸F]FET

Scheme 23. Generation of [¹⁸F]CF₃ Groups

Scheme 24. Radiosynthesis of [¹⁸F]FPPRGD2 and [¹⁸F]SFB

Scheme 25. Radiosyntheses via Thiol Functionalization

Scheme 26

Representative example of strain relief-promoted, copper-free click chemistry for ¹⁸F-radiolabeling. R = bombesin.

Scheme 27. Palladium-mediated Cross-coupling Reactions with Fluorine-18 including Sonogashira (a), Suzuki (b and C) and Stille (d and e) Reactions

Scheme 28. Photochemical Reactions with Fluorine-18

Scheme 29. Multicomponent Reactions with Fluorine-18

Scheme 30. Enzymatic Radiochemical Reactions Mediated by Fluorinase

Scheme 31. Fluorine-18 Acceptor Chemistry

Scheme 32. [¹⁸F]Sulfonyl Fluoride-based Prosthetic Groups

Scheme 33. Solid-phase synthesis of [¹⁸F]FluoroDOPA

Scheme 34. Solid-phase Synthesis of [¹⁸F]FDG

Scheme 35. Solid-phase Synthesis of [¹⁸F]Fluorouracil

Scheme 36. Solid-phase Synthesis of Fluorine-18 Labeled Prosthetic Groups