Flubatine

Flubatine ([18F]-norchloro-fluoro-homoepibatidine) is a fluorine-18 (¹⁸F) labeled radiotracer and radioligand for positron emission tomography (PET) imaging, developed as a high-affinity ligand for brain nicotinic acetylcholine receptors (nAChRs) of the α4β2 subtype.^[1]^[2] It is used to image cholinergic deficits in disorders such as Alzheimer’s disease and Parkinson’s disease.^[3] Both (+)- and (−)- enantiomer bind specifically to α4β2 nAChRs.^[4]

Synthesis

Flubatine is prepared by radiolabeling a precursor molecule with fluorine-18 under no-carrier-added conditions. The synthetic route involves two main steps:

Precursor synthesis: Optically pure precursor compounds (one for each enantiomer) are synthesized by organic chemical methods starting from epibatidine-like intermediates.^[1]
Radiolabeling: The [¹⁸F]fluoride ion is introduced by nucleophilic aromatic substitution of the precursor under controlled conditions (often using cryptand-assisted [¹⁸F]fluoride and heat).^[4] Using a trimethylammonium leaving group on the pyridine ring allows for efficient fluorination.

References

↑ ^1.0 ^1.1 "Synthesis and biological evaluation of both enantiomers of [(18)F]flubatine, promising radiotracers with fast kinetics for the imaging of α4β2-nicotinic acetylcholine receptors". Bioorganic & Medicinal Chemistry 22 (2): 804–812. 2014-01-15. doi:10.1016/j.bmc.2013.12.011. ISSN 1464-3391. PMID 24369841.
↑ "(+)-[18FFlubatine as a novel α4β2 nicotinic acetylcholine receptor PET ligand—results of the first-in-human brain imaging application in patients with β-amyloid PET-confirmed Alzheimer's disease and healthy controls"]. Eur. J. Nucl. Med. Mol. Imaging 48 (3): 731–746. 2020. doi:10.1007/s00259-020-05029-w. PMID 32935187.
↑ "Imaging of cerebral α4β2* nicotinic acetylcholine receptors with (-)-[(18)FFlubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain"]. NeuroImage 141: 71–80. 2016-11-01. doi:10.1016/j.neuroimage.2016.07.026. ISSN 1095-9572. PMID 27426839.
↑ ^4.0 ^4.1 "Exploring the Metabolism of (+)-[18FFlubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study †"] (in en). Molecules 23 (2). February 2018. doi:10.3390/molecule. ISSN 1420-3049. https://www.mdpi.com/1420-3049/23/2/464. Retrieved 2025-05-12.

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[:0-1] 1.0 ^1.1 "Synthesis and biological evaluation of both enantiomers of [(18)F]flubatine, promising radiotracers with fast kinetics for the imaging of α4β2-nicotinic acetylcholine receptors". Bioorganic & Medicinal Chemistry 22 (2): 804–812. 2014-01-15. doi:10.1016/j.bmc.2013.12.011. ISSN 1464-3391. PMID 24369841.

[2] "(+)-[18FFlubatine as a novel α4β2 nicotinic acetylcholine receptor PET ligand—results of the first-in-human brain imaging application in patients with β-amyloid PET-confirmed Alzheimer's disease and healthy controls"]. Eur. J. Nucl. Med. Mol. Imaging 48 (3): 731–746. 2020. doi:10.1007/s00259-020-05029-w. PMID 32935187.

[3] "Imaging of cerebral α4β2* nicotinic acetylcholine receptors with (-)-[(18)FFlubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain"]. NeuroImage 141: 71–80. 2016-11-01. doi:10.1016/j.neuroimage.2016.07.026. ISSN 1095-9572. PMID 27426839.

[:1-4] 4.0 ^4.1 "Exploring the Metabolism of (+)-[18FFlubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study †"] (in en). Molecules 23 (2). February 2018. doi:10.3390/molecule. ISSN 1420-3049. https://www.mdpi.com/1420-3049/23/2/464. Retrieved 2025-05-12.

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Flubatine

Topic: Medicine

Synthesis

References