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

Sabri, O., Becker, G.-A., Meyer, P. M., Hesse, S., Wilke, S., Graef, S., et al. (2015). First-in-human PET quantification study of cerebral α4β2* nicotinic acetylcholine receptors using the novel specific radioligand (−)-[18F]Flubatine. NeuroImage, 118, 199-208. doi:10.1016/j.neuroimage.2015.05.065.

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Sabri, Osama1, 2, Author
Becker, Georg-Alexander1, Author
Meyer, Philipp M.1, Author
Hesse, Swen1, 2, Author
Wilke, Stephan1, Author
Graef, Susanne3, 4, Author              
Patt, Marianne1, Author
Luthardt, Julia1, Author
Wagenknecht, Gudrun5, Author
Hoepping, Alexander6, Author
Smits, René6, Author
Franke, Annegret7, Author
Sattler, Bernhard1, Author
Habermann, Bernd1, Author
Neuhaus, Petra7, Author
Fischer, Steffen8, Author
Tiepolt, Solveig1, Author
Deuther-Conrad, Winnie8, Author
Barthel, Henryk1, Author
Schönknecht, Peter3, Author
Brust, Peter8, Author more..
1Department of Nuclear Medicine, University of Leipzig, Germany, ou_persistent22              
2Integrated Research and Treatment Center Adiposity Diseases, University of Leipzig, Germany, ou_persistent22              
3Department of Psychiatry, University of Leipzig, Germany, ou_persistent22              
4Max Planck Research Group Neurocognition of Decision Making, Max Planck Institute for Human Development, Max Planck Society, ou_2074295              
5Electronic Systems (ZEA-2), Central Institute for Engineering, Electronics and Analytics, Research Center Jülich, Germany, ou_persistent22              
6ABX Advanced Biochemical Compounds GmbH, Radeberg, Germany, ou_persistent22              
7Clinical Trial Centre Leipzig, University of Leipzig, Germany, ou_persistent22              
8Helmholtz Center Dresden-Rossendorf, Research Site Leipzig, Germany, ou_persistent22              


Free keywords: (−)-[18F]Flubatine [(−)-[18F]NCFHEB]; PET; α4β2* nicotinic acetylcholine receptors; Human brain; Kinetic modeling
 Abstract: α4β2* nicotinic receptors (α4β2* nAChRs) could provide a biomarker in neuropsychiatric disorders (e.g., Alzheimer's and Parkinson's diseases, depressive disorders, and nicotine addiction). However, there is a lack of α4β2* nAChR specific PET radioligands with kinetics fast enough to enable quantification of nAChR within a reasonable time frame. Following on from promising preclinical results, the aim of the present study was to evaluate for the first time in humans the novel PET radioligand (−)-[18F]Flubatine, formerly known as (−)-[18F]NCFHEB, as a tool for α4β2* nAChR imaging and in vivo quantification. Dynamic PET emission recordings lasting 270 min were acquired on an ECAT EXACT HR + scanner in 12 healthy male non-smoking subjects (71.0 ± 5.0 years) following the intravenous injection of 353.7 ± 9.4 MBq of (−)-[18F]Flubatine. Individual magnetic resonance imaging (MRI) was performed for co-registration. PET frames were motion-corrected, before the kinetics in 29 brain regions were characterized using 1- and 2-tissue compartment models (1TCM, 2TCM). Given the low amounts of metabolite present in plasma, we tested arterial input functions with and without metabolite corrections. In addition, pixel-based graphical analysis (Logan plot) was used. The model's goodness of fit, with and without metabolite correction was assessed by Akaike's information criterion. Model parameters of interest were the total distribution volume VT (mL/cm3), and the binding potential BPND relative to the corpus callosum, which served as a reference region. The tracer proved to have high stability in vivo, with 90% of the plasma radioactivity remaining as untransformed parent compound at 90 min, fast brain kinetics with rapid uptake and equilibration between free and receptor-bound tracer. Adequate fits of brain TACs were obtained with the 1TCM. VT could be reliably estimated within 90 min for all regions investigated, and within 30 min for low-binding regions such as the cerebral cortex. The rank order of VT by region corresponded well with the known distribution of α4β2* receptors (VT [thalamus] 27.4 ± 3.8, VT [putamen] 12.7 ± 0.9, VT [frontal cortex] 10.0 ± 0.8, and VT [corpus callosum] 6.3 ± 0.8). The BPND, which is a parameter of α4β2* nAChR availability, was 3.41 ± 0.79 for the thalamus, 1.04 ± 0.25 for the putamen and 0.61 ± 0.23 for the frontal cortex, indicating high specific tracer binding. Use of the arterial input function without metabolite correction resulted in a 10% underestimation in VT, and was without important biasing effects on BPND. Altogether, kinetics and imaging properties of (−)-[18F]Flubatine appear favorable and suggest that (−)-[18F]Flubatine is a very suitable and clinically applicable PET tracer for in vivo imaging of α4β2* nAChRs in neuropsychiatric disorders.


Language(s): eng - English
 Dates: 2014-10-022015-05-242015-05-302015-09
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.neuroimage.2015.05.065
PMID: 26037057
Other: Epub 2015
 Degree: -



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Title: NeuroImage
Source Genre: Journal
Publ. Info: Orlando, FL : Academic Press
Pages: - Volume / Issue: 118 Sequence Number: - Start / End Page: 199 - 208 Identifier: ISSN: 1053-8119
CoNE: https://pure.mpg.de/cone/journals/resource/954922650166