First-in-human PET quantification study of cerebral α4β2* nicotinic acetylcholine receptors using the novel specific radioligand (−)-[18F]Flubatine

Sabri, Osama; Becker, Georg-Alexander; Meyer, Philipp; Hesse, Swen; Wilke, Stephan; Graef, Susanne; Patt, Marianne; Luthardt, Julia; Wagenknecht, Gudrun; Hoepping, Alexander; Smits, René; Franke, Annegret; Sattler, Bernhard; Habermann, Bernd; Neuhaus, Petra; Fischer, Steffen; Tiepolt, Solveig; Deuther‐Conrad, Winnie; Barthel, Henryk; Schönknecht, Peter; Brust, Peter

doi:10.1016/j.neuroimage.2015.05.065

Cited by 52 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%

“…Because (−)-[ 18 F]flubatine exhibits a wide range of kinetic properties across different brain regions (Sabri et al, 2015), the infusion schedule was only optimized for regions with similar brain kinetics. We elected to determine the optimal K bol for cortical gray matter, as these regions are vital for interrogating acetylcholine's influence over memory and cognition.…”

Section: Methodsmentioning

confidence: 99%

“…First, the kinetic properties of 2-[ 18 F]FA-85380 and 5-[ 123 I]IA-85380 are slow and require lengthy imaging protocols of at least 5 h, presenting major logistical barriers to frequent imaging sessions. This has prompted the development of second-generation

α_{4} β_{2}^{*}

-nAChR specific radioligands, including [ 18 F]nifene (Hillmer et al, 2012), [ 18 F]AZAN (Wong et al, 2013), and (−)-[ 18 F]flubatine (Sabri et al, 2015), with faster kinetic properties and shorter scanning protocols. A second limitation is that conventional PET outcome measures of distribution volumes or binding potentials have restricted interpretation to ligand-receptor binding properties at equilibrium.…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Methodsmentioning

confidence: 99%

α_{4} β_{2}^{*}

Section: Introductionmentioning

confidence: 99%

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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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“…Novel radiotracers for imaging β2* (*denotes the presence of other subunits in the receptor composition, i.e. α4β2, α6α4β2, and α6β2) with faster kinetics and favorable binding parameters that have already been tested in humans include [ 18 F]AZAN 29 , [ 18 F]nifene 30 , (−)-[ 18 F]flubatine 31 and (+)-[ 18 F]Flubatine 32 .…”

Section: Pet Radiotracers That Have Enabled Imaging Of Neurotransmmentioning

confidence: 99%

News and views on in-vivo imaging of neurotransmission using PET and MRI

Sander

Hesse

2017

Q J Nucl Med Mol Imaging

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“…In particular, the serotonergic system has been receiving greater attention given the fact that a number of highly selective and specific radioligands are available for the quantification of major receptors, transporters, and enzymes of this system. Examples of the uses for PET/MRI in this domain include (i) prediction of drug response using serotonergic radiotracers (drug occupancy, pharmacological interaction with fMRI, and hormonal interactions with brain function) and frequently prescribed antidepressants as selective serotonin reuptake inhibitors, (ii) the combination of PET + MRI + EEG to combine higher spatial and temporal resolution measurements, and (iii) the introduction of α 4 β 2 cholinergic receptor radioligands [14]. Recent studies have also shown that dopamine agonists and antagonists induce opposite effects on cerebral blood flow providing important insights into neurovascular coupling [15, 16].…”

Section: Dialogue Board 1: Neurosciencesmentioning

confidence: 99%

Combined PET/MRI: from Status Quo to Status Go. Summary Report of the Fifth International Workshop on PET/MR Imaging; February 15–19, 2016; Tübingen, Germany

et al. 2016

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This article provides a collaborative perspective of the discussions and conclusions from the fifth international workshop of combined positron emission tomorgraphy (PET)/magnetic resonance imaging (MRI) that was held in Tübingen, Germany, from February 15 to 19, 2016. Specifically, we summarise the second part of the workshop made up of invited presentations from active researchers in the field of PET/MRI and associated fields augmented by round table discussions and dialogue boards with specific topics. This year, this included practical advice as to possible approaches to moving PET/MRI into clinical routine, the use of PET/MRI in brain receptor imaging, in assessing cardiovascular diseases, cancer, infection, and inflammatory diseases. To address perceived challenges still remaining to innovatively integrate PET and MRI system technologies, a dedicated round table session brought together key representatives from industry and academia who were engaged with either the conceptualisation or early adoption of hybrid PET/MRI systems. Discussions during the workshop highlighted that emerging unique applications of PET/MRI such as the ability to provide multi-parametric quantitative and visual information which will enable not only overall disease detection but also disease characterisation would eventually be regarded as compelling arguments for the adoption of PET/MR. However, as indicated by previous workshops, evidence in favour of this observation is only growing slowly, mainly due to the ongoing inability to pool data cohorts from independent trials as well as different systems and sites. The participants emphasised that moving from status quo to status go entails the need to adopt standardised imaging procedures and the readiness to act together prospectively across multiple PET/MRI sites and vendors.

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First-in-human PET quantification study of cerebral α4β2* nicotinic acetylcholine receptors using the novel specific radioligand (−)-[18F]Flubatine

Cited by 52 publications

References 50 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

News and views on in-vivo imaging of neurotransmission using PET and MRI

Combined PET/MRI: from Status Quo to Status Go. Summary Report of the Fifth International Workshop on PET/MR Imaging; February 15–19, 2016; Tübingen, Germany

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