title: First-in-human PET quantification study of cerebral α4β2* nicotinic acetylcholine receptors using the novel specific radioligand (-)-[(18)F]Flubatine.
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 (-)-[(18)F]Flubatine, formerly known as (-)-[(18)F]NCFHEB, as a tool for α4β2* nAChR imaging and in vivo quantification. Dynamic PET emission recordings lasting 270min were acquired on an ECAT EXACT HR+ scanner in 12 healthy male non-smoking subjects (71.0±5.0years) following the intravenous injection of 353.7±9.4MBq of (-)-[(18)F]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/cm(3)), 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 90min, 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 90min for all regions investigated, and within 30min 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 (-)-[(18)F]Flubatine appear favorable and suggest that (-)-[(18)F]Flubatine is a very suitable and clinically applicable PET tracer for in vivo imaging of α4β2* nAChRs in neuropsychiatric disorders.
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany; Integrated Research and Treatment Centre (IFB) Adiposity Diseases, University of Leipzig, Philipp-Rosenthal-Straße 27, 04103 Leipzig, Germany. Electronic address: Osama.Sabri@medizin.uni-leipzig.de.
authors.forename: Osama
authors.initials: O
authors.lastname: Sabri
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
authors.forename: Georg-Alexander
authors.initials: GA
authors.lastname: Becker
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Meyer
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany; Integrated Research and Treatment Centre (IFB) Adiposity Diseases, University of Leipzig, Philipp-Rosenthal-Straße 27, 04103 Leipzig, Germany.
authors.forename: Swen
authors.initials: S
authors.lastname: Hesse
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wilke
authors.affiliation: Department of Psychiatry, University of Leipzig, Semmelweisstraße 10, 04103 Leipzig, Germany; Max-Planck-Institute for Human Cognitive and Brain Sciences, Stephanstraße 1a, 04103 Leipzig, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Graef
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Patt
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Luthardt
authors.affiliation: Electronic Systems (ZEA-2), Central Institute for Engineering, Electronics and Analytics, Research Centre Juelich, Wilhelm-Johnen-Straße, 52428 Juelich, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Wagenknecht
authors.affiliation: ABX Advanced Biochemical Compounds GmbH, Heinrich-Gläser-Straße 10, 01454 Radeberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoepping
authors.affiliation: ABX Advanced Biochemical Compounds GmbH, Heinrich-Gläser-Straße 10, 01454 Radeberg, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Smits
authors.affiliation: Clinical Trial Centre Leipzig, Härtelstraße 16-18, 04107 Leipzig, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Sattler
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Habermann
authors.affiliation: Clinical Trial Centre Leipzig, Härtelstraße 16-18, 04107 Leipzig, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Neuhaus
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
authors.forename: Solveig
authors.initials: S
authors.lastname: Tiepolt
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
authors.forename: Henryk
authors.initials: H
authors.lastname: Barthel
authors.affiliation: Department of Psychiatry, University of Leipzig, Semmelweisstraße 10, 04103 Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schönknecht
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
mesh_terms: D000368:Aged; D001549:Benzamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods*; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011978:Receptors, Nicotinic; C115362:fluoronorchloroepibatidine; C403531:nicotinic receptor alpha4beta2
keywords: (−)-[(18)F]Flubatine [(−)-[(18)F]NCFHEB]; Human brain; Kinetic modeling; PET; α4β2* nicotinic acetylcholine receptors