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.
Highlights
Both enantiomers (+)-[18 F]flubatine ((+)-(1S,5R,6R)-6-(6-[18 F]fluoro-pyridine-3-yl)-8-azabicyclo[3.2.1]octane, (+)-[18 F]1, Figure 1) and (−)-[18 F]flubatine ((−)-[18 F]1) are radioligands for imaging of α4β2 nicotinic acetylcholine receptors in brain by positron emission tomography (PET).Their development starting from the alkaloid (−)-epibatidine [1], originally isolated from the poison dart frog Epipedobates anthonyi, has been widely reported [2,3,4]
For the determination of the fraction of unchanged tracer, samples of arterial blood are collected, prepared, and analyzed by high performance liquid chromatography followed by online radioactive
This is in accordance with the previously reported NADPH-dependent degradation by HLM and microsomesoffrom humans (HLM) and mice (MLM) [4], while the metabolite pattern originating from pigs was more metabolism pathways in pig
Summary
Both enantiomers (+)-[18 F]flubatine ((+)-(1S,5R,6R)-6-(6-[18 F]fluoro-pyridine-3-yl)-8-azabicyclo[3.2.1]octane, (+)-[18 F]1, Figure 1) and (−)-[18 F]flubatine ((−)-[18 F]1) are radioligands for imaging of α4β2 nicotinic acetylcholine receptors (nAChRs) in brain by positron emission tomography (PET). Their development starting from the alkaloid (−)-epibatidine [1], originally isolated from the poison dart frog Epipedobates anthonyi, has been widely reported [2,3,4]. In human, (−)-[18 F]1 showed a high metabolic stability 22, 464 [9].
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