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Molecules 2018, 23(2), 464; https://doi.org/10.3390/molecules23020464

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

1
Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, 04318 Leipzig, Germany
2
ABX advanced biochemical compounds GmbH, Heinrich-Gläser-Straße 10-14, 01454 Radeberg, Germany
3
Department of Nuclear Medicine, University Hospital Leipzig, Liebigstraße 18, 04103 Leipzig, Germany
This publication is dedicated to Jörg Steinbach on the occasion of his 65th birthday.
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 29 January 2018 / Revised: 15 February 2018 / Accepted: 16 February 2018 / Published: 20 February 2018
(This article belongs to the Special Issue Current Aspects of Radiopharmaceutical Chemistry)
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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. In pigs, (+)-1 was monohydroxylated at different sites of the azabicyclic ring system of the molecule. Additionally, one intermediate metabolite underwent glucuronidation, as also demonstrated in vitro. In humans, a fraction of 95.9 ± 1.9% (n = 10) of unchanged tracer remained in plasma, 30 min after injection. However, despite the low metabolic degradation, both radiometabolites formed in humans could be characterized as (i) a product of C-hydroxylation at the azabicyclic ring system, and (ii) a glucuronide conjugate of the precedingly-formed N8-hydroxylated (+)-[18F]1. View Full-Text
Keywords: [18F]flubatine; NCFHEB; [18F]FLBT; radiometabolites; glucuronides; liquid chromatography–tandem mass spectrometry (LC-MS/MS); liver microsomes; positron emission tomography (PET); nicotinic acetylcholine receptors (nAChRs) [18F]flubatine; NCFHEB; [18F]FLBT; radiometabolites; glucuronides; liquid chromatography–tandem mass spectrometry (LC-MS/MS); liver microsomes; positron emission tomography (PET); nicotinic acetylcholine receptors (nAChRs)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Ludwig, F.-A.; Fischer, S.; Smits, R.; Deuther-Conrad, W.; Hoepping, A.; Tiepolt, S.; Patt, M.; Sabri, O.; Brust, P. Exploring the Metabolism of (+)-[18F]Flubatine In Vitro and In Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study . Molecules 2018, 23, 464.

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