Hydrogen-bond promoted nucleophilic fluorination: concept, mechanism and applications in positron emission tomography

This Tutorial Review summarizes the recent breakthroughs in SN2-type nucleophilic fluorination reactions using alkali metal fluorides promoted by protic solvents, inducing excellent selectivity and high reaction rates.

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ChemInform Abstract: Hydrogen-Bond Promoted Nucleophilic Fluorination: Concept, Mechanism and Applications in Positron Emission Tomography

ChemInform ◽

10.1002/chin.201643200 ◽

2016 ◽

Vol 47 (43) ◽

Author(s):

Ji-Woong Lee ◽

Maria Teresa Oliveira ◽

Hyeong Bin Jang ◽

Sungyul Lee ◽

Dae Yoon Chi ◽

...

Keyword(s):

Positron Emission Tomography ◽

Hydrogen Bond ◽

Emission Tomography ◽

Positron Emission ◽

Nucleophilic Fluorination

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Reaction of [18F]Fluoride at Heteroatoms and Metals for Imaging of Peptides and Proteins by Positron Emission Tomography

Frontiers in Chemistry ◽

10.3389/fchem.2021.687678 ◽

2021 ◽

Vol 9 ◽

Author(s):

Kymberley R. Scroggie ◽

Michael V. Perkins ◽

Justin M. Chalker

Keyword(s):

Positron Emission Tomography ◽

Bond Formation ◽

Emission Tomography ◽

Indirect Methods ◽

Native Proteins ◽

Direct Fluorination ◽

Positron Emission ◽

Aqueous Environments ◽

Prosthetic Groups ◽

Nucleophilic Fluorination

The ability to radiolabel proteins with [18F]fluoride enables the use of positron emission tomography (PET) for the early detection, staging and diagnosis of disease. The direct fluorination of native proteins through C-F bond formation is, however, a difficult task. The aqueous environments required by proteins severely hampers fluorination yields while the dry, organic solvents that promote nucleophilic fluorination can denature proteins. To circumvent these issues, indirect fluorination methods making use of prosthetic groups that are first fluorinated and then conjugated to a protein have become commonplace. But, when it comes to the radiofluorination of proteins, these indirect methods are not always suited to the short half-life of the fluorine-18 radionuclide (110 min). This review explores radiofluorination through bond formation with fluoride at boron, metal complexes, silicon, phosphorus and sulfur. The potential for these techniques to be used for the direct, aqueous radiolabeling of proteins with [18F]fluoride is discussed.

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Applications of iodonium salts and iodonium ylides as precursors for nucleophilic fluorination in Positron Emission Tomography

ARKIVOC ◽

10.3998/ark.5550190.p008.225 ◽

2013 ◽

Vol 2013 (1) ◽

pp. 364-395 ◽

Cited By ~ 35

Author(s):

Mekhman S. Yusubov ◽

Dmitrii Yu. Svitich ◽

Mariia S. Larkina ◽

Viktor V. Zhdankin

Keyword(s):

Positron Emission Tomography ◽

Emission Tomography ◽

Iodonium Salts ◽

Positron Emission ◽

Iodonium Ylides ◽

Nucleophilic Fluorination

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Preparation of the Serotonin Transporter PET Radiotracer 2-({2-[(Dimethylamino)methyl]phenyl}thio)-5-[18F]fluoroaniline (4-[18F]ADAM): Probing Synthetic and Radiosynthetic Methods

Synthesis ◽

10.1055/s-0039-1690522 ◽

2019 ◽

Vol 51 (23) ◽

pp. 4374-4384

Author(s):

Selena Milicevic Sephton ◽

Xiaoyun Zhou ◽

Stephen Thompson ◽

Franklin I. Aigbirhio

Keyword(s):

Positron Emission Tomography ◽

Emission Tomography ◽

Synthetic Route ◽

Positron Emission ◽

Amide Coupling ◽

Good Target ◽

Monitoring Treatment ◽

Hydrolysis Of ◽

Nucleophilic Fluorination ◽

Methyl Phenyl

Serotonin transporters (SERTs) are involved in regulating the concentration of synaptic serotonin and present a good target for many neurologic and psychiatric disorder drugs. Positron-emission tomography (PET) is a valuable tool in both diagnosis and monitoring treatment therapies, and hence much effort is being given to developing suitable PET agents for imaging SERT. Our interest in applying the fluorine-18 analogue 4-[18F]ADAM for imaging SERT prompted the development of an improved synthetic route to access unlabelled ADAM. This is achieved using Pd-catalysed coupling with thiosalicylic acid and an EDC/HOBt amide coupling in 36% yield over 4 steps. A novel radiolabelling precursor, the pinacol-derived boronic ester, is prepared from the bromide using the Miyaura borylation and is obtained in 27% yield over 6 steps. Pinacolate is then used for the radiolabelling of 4-[18F]ADAM based on Cu-mediated nucleophilic fluorination in which the presence of oxygen is critical for the reaction. A 1:1 substrate to copper ratio is found to be optimal when the reaction is performed in dimethylacetamide at 85 °C. Using these conditions, 4-[18F]ADAM is prepared in 29 ± 10% (n = 6) radiochemical conversion after hydrolysis of the Boc group with HCl. Furthermore, the method is successfully automated to afford 4-[18F]ADAM in 10% radiochemical conversion.

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