Journal
NEUROIMAGE
Volume 118, Issue -, Pages 199-208Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.neuroimage.2015.05.065
Keywords
(-)-[F-18]Flubatine [(-)-[F-18]NCFHEB]; PET; alpha 4 beta 2*nicotinic acetylcholine receptors; Human brain; Kinetic modeling
Funding
- BMBF grant (German Federal Ministry of Education and Research) [01EZ0820, 01EZ0821, 01EZ0822, 01EZ0823]
- International Max Planck Research School on Neuroscience of Communication (IMPRS NeuroCom)
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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 (-)-[F-18]Flubatine, formerly known as (-)-[F-18]NCFHEB, as a tool for alpha 4 beta 2* 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 (-)-[F-18]Flubatine. Individual magnetic resonance imaging (MRI) was performed for coregistration. 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 V-T (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 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. V-T 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 V-T by region corresponded well with the known distribution of alpha 4 beta 2* receptors (V-T [thalamus] 27.4 +/- 3.8, V-T [putamen] 12.7 +/- 0.9, V-T [frontal cortex] 10.+/- 0.8, and V-T [corpus callosum]6.3 +/- 0.8). The BPND, which is a parameter of alpha 4 beta 2* 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 V-T, and was without important biasing effects on BPND. Altogether, kinetics and imaging properties of (-)-[F-18] Flubatine appear favorable and suggest that (-)[F-18] Flubatine is a very suitable and clinically applicable PET tracer for in vivo imaging of alpha 4 beta 2* nAChRs in neuropsychiatric disorders. (C) 2015 Elsevier Inc. All rights reserved.
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