Exploring the Metabolism of (+)-[18F]Flubatine in Vitro and in Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study.

Abstract

Both (+)-[18F]flubatine and its enantiomer (-)-[18F]flubatine are radioligands for the neuroimaging of α4β2 nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET). In a clinical study in patients with early Alzheimer's disease, (+)-[18F]flubatine ((+)-[18F]1) was examined regarding its metabolic fate, in particular by identification of degradation products detected in plasma and urine. The investigations included an in vivo study of (+)-flubatine ((+)-1) in pigs and structural elucidation of formed metabolites by LC-MS/MS. Incubations of (+)-1 and (+)-[18F]1 with human liver microsomes were performed to generate in vitro metabolites, as well as radiometabolites, which enabled an assignment of their structures by comparison of LC-MS/MS and radio-HPLC data. Plasma and urine samples taken after administration of (+)-[18F]1 in humans were examined by radio-HPLC and, on the basis of results obtained in vitro and in vivo, formed radiometabolites were identified.

• Authors: Friedrich-Alexander Ludwig, Steffen Fischer, René Smits, Winnie Deuther-Conrad, Alexander Hoepping, Solveig Tiepolt, Marianne Patt, Osama Sabri, Peter Brust
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 23 Issue 2 (Feb 20 2018) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 29461507 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Bridged Bicyclo Compounds, Heterocyclic
• Receptors, Nicotinic
• fluoronorchloroepibatidine

Topics

• Animals
• Benzamides (administration & dosage, metabolism)
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage, metabolism)
• Chromatography, Liquid
• Humans
• Metabolome (genetics)
• Neuroimaging
• Positron-Emission Tomography
• Receptors, Nicotinic (chemistry, isolation & purification)
• Swine (blood, urine)
• Tandem Mass Spectrometry