Evaluation of metabolism, plasma protein binding and other biological parameters after administration of (−)-[18F]Flubatine in humans

Patt, Marianne; Becker, Georg; Grossmann, Udo; Habermann, Bernd; Schildan, Andreas; Wilke, Stephan; Deuther‐Conrad, Winnie; Graef, Susanne; Fischer, Steffen; Smits, René; Hoepping, Alexander; Wagenknecht, Gudrun; Steinbach, Jörg; Gertz, Hermann‐Josef; Hesse, Swen; Schönknecht, Peter; Brust, Peter; Sabri, Osama

doi:10.1016/j.nucmedbio.2014.03.018

Cited by 17 publications

(22 citation statements)

References 14 publications

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“…First-in-human characterizations of (−)-[ 18 F]flubatine in both arterial plasma (Patt et al, 2014) and tissue with thorough kinetic analysis with compartment modeling (Sabri et al, 2015) were recently reported. Our present analysis of this radiotracer confirms many of these findings, including similar behavior in arterial blood, comparable V T and f P values, and a similar V T rank order across gray matter regions.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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The positron emission tomography (PET) radioligand (−)-[18F]flubatine is specific to α4β2∗ nicotinic acetylcholine receptors (nAChRs) and has promise for future investigation of the acetylcholine system in neuropathologies such as Alzheimer's disease, schizophrenia, and substance use disorders. The two goals of this work were to develop a simplified method for α4β2∗ nAChR quantification with bolus plus constant infusion (B/I) (−)-[18F]flubatine administration, and to assess the radioligand's sensitivity to acetylcholine fluctuations in humans. Healthy human subjects were imaged following either bolus injection (n = 8) or B/I (n = 4) administration of (−)-[18F]flubatine. The metabolite-corrected input function in arterial blood was measured. Free-fraction corrected distribution volumes (VT/fP) were estimated with modeling and graphical analysis techniques. Next, sensitivity to acetylcholine was assessed in two ways: 1. A bolus injection paradigm with two scans (n = 6), baseline (scan 1) and physostigmine challenge (scan 2; 1.5 mg over 60 min beginning 5 min prior to radiotracer injection); 2. A single scan B/I paradigm (n = 7) lasting up to 240 min with 1.5 mg physostigmine administered over 60 min beginning at 125 min of radiotracer infusion. Changes in VT/fP were measured. Baseline VT/fP values were 33.8 ± 3.3 mL/cm3 in thalamus, 12.9 ± 1.6 mL/cm3 in cerebellum, and ranged from 9.8 to 12.5 mL/cm3 in other gray matter regions. The B/I paradigm with equilibrium analysis at 120 min yielded comparable VT/fP values with compartment modeling analysis of bolus data in extrathalamic gray matter regions (regional means <4% different). Changes in VT/fP following physostigmine administration were small and most pronounced in cortical regions, ranging from 0.8 to 4.6% in the two-scan paradigm and 2.8 to 6.5% with the B/I paradigm. These results demonstrate the use of B/I administration for accurate quantification of (−)-[18F]flubatine VT/fP in 120 min, and suggest possible sensitivity of (−)-[18F]flubatine binding to physostigmine-induced changes in acetylcholine levels.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…PET and blood data processing were performed as recently described in detail. In the current data analysis only 0 to 90 min dynamic data were used since kinetic data analysis has shown that analysis of 0 to 90 min dynamic data allows accurate quantification of all brain regions ( Patt et al , 2014 ; Sabri et al , 2015 ). In brief, tissue time activity curves from 0 to 90 min were used for kinetic analysis with a one-tissue compartment model to calculate the total distribution volume (V T ).…”

Section: Methodsmentioning

confidence: 99%

Cognitive correlates of α4β2 nicotinic acetylcholine receptors in mild Alzheimer’s dementia

Sabri

Meyer

Gräf

et al. 2018

Brain

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Whether α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) expression is reduced in early Alzheimer’s disease is controversial. Using (-)-[18F]Flubatine PET, Sabri, Meyer et al. report α4β2-nAChR deficiency in mild Alzheimer’s dementia, especially within the basal forebrain-cortical and septohippocampal cholinergic projections. Reduced α4β2-nAChR availability correlates with impaired episodic memory and executive function/working memory.

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“…50 Tracer binding to plasma proteins in human blood was demonstrated in vitro and ex vivo to show no differences between patients with Alzheimer’s disease and healthy controls. 51 [ 11 C]CHIBA-1001 is a PET radiotracer for the α-7 subtype of nAChR. 52 The tracer demonstrated has low specific binding for the α-7 subtype.…”

Section: Nicotinic Acetylcholine Receptormentioning

confidence: 99%

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

Kassenbrock¹,

Vasdev²,

Liang

2016

CTMC

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Positron emission tomography (PET) neuroimaging of ion channel linked receptors is a developing area of preclinical and clinical research. The present review focuses on recent advances with radiochemistry, preclinical and clinical PET imaging studies of three receptors that are actively pursued in neuropsychiatric drug discovery: namely the γ-aminobutyric acid-benzodiazapine (GABA) receptor, nicotinic acetylcholine receptor (nAChR), and N-methyl-d-aspartate (NMDA) receptor. Recent efforts to develop new PET radioligands for these targets with improved brain uptake, selectivity, stability and pharmacokinetics are highlighted.

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Evaluation of metabolism, plasma protein binding and other biological parameters after administration of (−)-[18F]Flubatine in humans

Cited by 17 publications

References 14 publications

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

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

Cognitive correlates of α4β2 nicotinic acetylcholine receptors in mild Alzheimer’s dementia

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

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