Imaging of cerebral α4β2* nicotinic acetylcholine receptors with (−)-[18F]Flubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain

Hillmer, Ansel T.; Esterlis, Irina; Gallezot, Jean‐Dominique; Bois, Frédéric; Zheng, Ming-Qiang; Nabulsi, Nabeel; Lin, Shu-fei; Papke, Roger L.; Huang, Yiyun; Sabri, Osama; Carson, Richard E.; Cosgrove, Kelly P.

doi:10.1016/j.neuroimage.2016.07.026

Cited by 62 publications

(55 citation statements)

References 56 publications

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“…The presented results should be seen in the context of previous metabolism studies on both enantiomers of flubatine and [ 18 F]flubatine [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. In particular, the characterisation of phase I metabolites of (+)- 1 formed by HLM and MLM, as well as the assignment of corresponding incubated with radiometabolites in mouse, published by our group [ 4 ], are highly relevant for the discussion.…”

Section: Discussionmentioning

confidence: 53%

“…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 the framework of preclinical and clinical studies, the metabolism of (−)-[ 18 F] 1 in pigs [ 5 ], rhesus monkeys [ 6 , 7 , 8 ], and in humans [ 3 , 9 , 10 , 11 ] was examined mainly with the purpose of determination of the fraction of unchanged tracer over time to enable a metabolite correction of the PET data obtained. In human, (−)-[ 18 F] 1 showed a high metabolic stability [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…This difference was small since only a low dose to avoid peripheral side effects. However, this finding suggested that (−)-18 F-Flubatine is probably sensitive to changes in acetylcholine levels in humans (Hillmer et al 2016a).…”

Section: (−)-18 F-flubatinementioning

confidence: 98%

Nicotinic Acetylcholine Receptor Signaling in Neuroprotection

Akaike

Shimohama

Misu

2018

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“…These preclinical investigations suggest that sensitivity for measuring changes of extracellular acetylcholine could feasible with all these tracers. In keeping with this assumption, a recent study in humans demonstrated the use of bolus/infusion protocol for accurate quantification of (−)-[ 18 F]flubatine binding parameters in 120 min of physostigmine-induced changes in acetylcholine levels 94 suitable for future application in clinical studies.…”

Section: Types Of Challenges That Modulate Neurotransmission and mentioning

confidence: 98%