First-in-human PET quantification study of cerebral α4ß2* nicotinic acetylcholine receptors using the novel specific radioligand (-)-[(18)F]Flubatine.

α4ß2* nicotinic receptors (α4ß2* 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 α4ß2* 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 α4ß2* 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 α4ß2* 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 α4ß2* 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 α4ß2* nAChRs in neuropsychiatric disorders.

Evaluation of metabolism, plasma protein binding and other biological parameters after administration of (-)-[(18)F]Flubatine in humans.

INTRODUCTION: (-)-[(18)F]Flubatine is a PET tracer with high affinity and selectivity for the nicotinic acetylcholine α4ß2 receptor subtype. A clinical trial assessing the availability of this subtype of nAChRs was performed. From a total participant number of 21 Alzheimer's disease (AD) patients and 20 healthy controls (HCs), the following parameters were determined: plasma protein binding, metabolism and activity distribution between plasma and whole blood. METHODS: Plasma protein binding and fraction of unchanged parent compound were assessed by ultracentrifugation and HPLC, respectively. The distribution of radioactivity (parent compound+metabolites) between plasma and whole blood was determined ex vivo at different time-points after injection by gamma counting after separation of whole blood by centrifugation into the cellular and non-cellular components. In additional experiments in vitro, tracer distribution between these blood components was assessed for up to 90min. RESULTS: A fraction of 15%±2% of (-)-[(18)F]Flubatine was found to be bound to plasma proteins. Metabolic degradation of (-)-[(18)F]Flubatine was very low, resulting in almost 90% unchanged parent compound at 90min p.i. with no significant difference between AD and HC. The radioactivity distribution between plasma and whole blood changed in vivo only slightly over time from 0.82±0.03 at 3min p.i. to 0.87±0.03 at 270min p.i. indicating the contribution of only a small amount of metabolites. In vitro studies revealed that (-)-[(18)F]Flubatine was instantaneously distributed between cellular and non-cellular blood parts. DISCUSSION: (-)-[(18)F]Flubatine exhibits very favourable characteristics for a PET radiotracer such as slow metabolic degradation and moderate plasma protein binding. Equilibrium of radioactivity distribution between plasma and whole blood is reached instantaneously and remains almost constant over time allowing both convenient sample handling and facilitated fractional blood volume contribution assessment.

Using the Rey Auditory Verbal Learning Test (RAVLT) to differentiate alzheimer's dementia and behavioural variant fronto-temporal dementia.

In patients with focal lesions, patterns of learning, retrieval, and recognition deficits vary according to site of damage. Because different brain regions are affected by the underlying pathology in Alzheimer's dementia (AD) and behavioral variant fronto-temporal dementia (bvFTD), one might predict that the two disorders would result in different sorts of memory deficits on the Rey Auditory Verbal Learning Test (RAVLT). The aim of this investigation was to find a way to differentiate AD, bvFTD, and normal controls (NC) reliably based on RAVLT scores from retrospective samples of 82 Italian and 43 Australian participants. Results indicated that the groups differed on measures of learning, retroactive interference, delayed recall, and delayed recognition. Although delayed recall distinguished participants in the three groups across both samples, no one set of cut-offs could be obtained with adequate sensitivity and specificity. However, when we created a combined score (the "RAVLT Memory Efficiency Index": {[(delayed recall A/15)/(RAVLT Trials 1-5/75)] + [(delayed recognition hits/15) - (false positive/total number of distractors)]}), we were able to find cut-offs that differentiated the groups with good sensitivity and specificity across variations in RAVLT methodology, participant samples, and languages. This index will increase the usefulness of the RAVLT in differential diagnoses of early dementia.

Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: an overview of preclinical and clinical findings.

RATIONALE: The cholinergic system has long been linked to cognitive processes. Two main classes of acetylcholine (ACh) receptors exist in the human brain, namely muscarinic and nicotinic receptors, of which several subtypes occur. OBJECTIVES: This review seeks to provide an overview of previous findings on the influence of cholinergic receptor manipulations on cognition in animals and humans, with particular emphasis on the role of selected cholinergic receptor subtypes. Furthermore, the involvement of these receptor subtypes in the regulation of emotion and brain electrical activity as measured by electroencephalography (EEG) shall be addressed since these domains are considered to be important modulators of cognitive functioning. RESULTS: In regard to cognition, the muscarinic receptor subtypes have been implicated mainly in memory functions, but have also been linked to attentional processes. The nicotinic α7 receptor subtype is involved in working memory, whereas the α4ß2* subtype has been linked to tests of attention. Both muscarinic and nicotinic cholinergic mechanisms play a role in modulating brain electrical activity. Nicotinic receptors have been strongly associated with the modulation of depression and anxiety. CONCLUSIONS: Cholinergic receptor manipulations have an effect on cognition, emotion, and brain electrical activity as measured by EEG. Changes in cognition can result from direct cholinergic receptor manipulation or from cholinergically induced changes in vigilance or affective state.

Differential influence of levodopa on reward-based learning in Parkinson's disease.

The mesocorticolimbic dopamine (DA) system linking the dopaminergic midbrain to the prefrontal cortex and subcortical striatum has been shown to be sensitive to reinforcement in animals and humans. Within this system, coexistent segregated striato-frontal circuits have been linked to different functions. In the present study, we tested patients with Parkinson's disease (PD), a neurodegenerative disorder characterized by dopaminergic cell loss, on two reward-based learning tasks assumed to differentially involve dorsal and ventral striato-frontal circuits. 15 non-depressed and non-demented PD patients on levodopa monotherapy were tested both on and off medication. Levodopa had beneficial effects on the performance on an instrumental learning task with constant stimulus-reward associations, hypothesized to rely on dorsal striato-frontal circuits. In contrast, performance on a reversal learning task with changing reward contingencies, relying on ventral striato-frontal structures, was better in the unmedicated state. These results are in line with the "overdose hypothesis" which assumes detrimental effects of dopaminergic medication on functions relying upon less affected regions in PD. This study demonstrates, in a within-subject design, a double dissociation of dopaminergic medication and performance on two reward-based learning tasks differing in regard to whether reward contingencies are constant or dynamic. There was no evidence for a dose effect of levodopa on reward-based behavior with the patients' actual levodopa dose being uncorrelated to their performance on the reward-based learning tasks.