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Molecules 2016, 21(9), 1200; doi:10.3390/molecules21091200

LC-MS Supported Studies on the in Vitro Metabolism of both Enantiomers of Flubatine and the in Vivo Metabolism of (+)-[18F]Flubatine—A Positron Emission Tomography Radioligand for Imaging α4β2 Nicotinic Acetylcholine Receptors

1
Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany
2
ABX Advanced Biochemical Compounds GmbH, Heinrich-Gläser-Straße 10-14, Radeberg 01454, Germany
3
Division of Brain Sciences, Imperial College London, Du Cane Road, London W12 0NN, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Zhen Cheng
Received: 8 August 2016 / Revised: 1 September 2016 / Accepted: 2 September 2016 / Published: 8 September 2016
(This article belongs to the Special Issue Molecular Imaging Probes)
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Abstract

Both enantiomers of [18F]flubatine are promising radioligands for neuroimaging of α4β2 nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET). To support clinical studies in patients with early Alzheimer’s disease, a detailed examination of the metabolism in vitro and in vivo has been performed. (+)- and (−)-flubatine, respectively, were incubated with liver microsomes from mouse and human in the presence of NADPH (β-nicotinamide adenine dinucleotide 2′-phosphate reduced tetrasodium salt). Phase I in vitro metabolites were detected and their structures elucidated by LC-MS/MS (liquid chromatography-tandem mass spectrometry). Selected metabolite candidates were synthesized and investigated for structural confirmation. Besides a high level of in vitro stability, the microsomal incubations revealed some species differences as well as enantiomer discrimination with regard to the formation of monohydroxylated products, which was identified as the main metabolic pathway in this assay. Furthermore, after injection of 250 MBq (+)-[18F]flubatine (specific activity > 350 GBq/μmol) into mouse, samples were prepared from brain, liver, plasma, and urine after 30 min and investigated by radio-HPLC (high performance liquid chromatography with radioactivity detection). For structure elucidation of the radiometabolites of (+)-[18F]flubatine formed in vivo, identical chromatographic conditions were applied to LC-MS/MS and radio-HPLC to compare samples obtained in vitro and in vivo. By this correlation approach, we assigned three of four main in vivo radiometabolites to products that are exclusively C- or N-hydroxylated at the azabicyclic ring system of the parent molecule. View Full-Text
Keywords: nicotinic acetylcholine receptors (nAChRs); epibatidine; flubatine; NCFHEB; positron emission tomography (PET); radiometabolites; liquid chromatography-mass spectrometry (LC-MS); liver microsomes nicotinic acetylcholine receptors (nAChRs); epibatidine; flubatine; NCFHEB; positron emission tomography (PET); radiometabolites; liquid chromatography-mass spectrometry (LC-MS); liver microsomes
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MDPI and ACS Style

Ludwig, F.-A.; Smits, R.; Fischer, S.; Donat, C.K.; Hoepping, A.; Brust, P.; Steinbach, J. LC-MS Supported Studies on the in Vitro Metabolism of both Enantiomers of Flubatine and the in Vivo Metabolism of (+)-[18F]Flubatine—A Positron Emission Tomography Radioligand for Imaging α4β2 Nicotinic Acetylcholine Receptors. Molecules 2016, 21, 1200.

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