Details

Autor(en) / Beteiligte

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

Titel

First-in-human PET quantification study of cerebral alpha 4 beta 2 nicotinic acetylcholine receptors using the novel specific radioligand (-)-[18F]Flubatine

Ist Teil von

• NeuroImage (Orlando, Fla.), 2015-09, Vol.118, p.199-208

Erscheinungsjahr

2015

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• alpha 4 beta 2* nicotinic receptors ( alpha 4 beta 2* 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 alpha 4 beta 2* 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 alpha 4 beta 2* 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 plus or minus 5.0years) following the intravenous injection of 353.7 plus or minus 9.4MBq 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 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 alpha 4 beta 2* receptors (VT [thalamus] 27.4 plus or minus 3.8, VT [putamen] 12.7 plus or minus 0.9, VT [frontalcortex] 10.0 plus or minus 0.8, and VT [corpuscallosum] 6.3 plus or minus 0.8). The BPND, which is a parameter of alpha 4 beta 2* nAChR availability, was 3.41 plus or minus 0.79 for the thalamus, 1.04 plus or minus 0.25 for the putamen and 0.61 plus or minus 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 alpha 4 beta 2* nAChRs in neuropsychiatric disorders.