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The reproducibility of findings is a compelling methodological problem that the neuroimaging community is facing these days. The lack of standardized pipelines for image processing, quantification and statistics plays a major role in the variability and interpretation of results, even when the same data are analysed. This problem is well-known in MRI studies, where the indisputable value of the method has been complicated by a number of studies that produce discrepant results. However, any research domain with complex data and flexible analytical procedures can experience a similar lack of reproducibility. In this paper we investigate this issue for brain PET imaging. During the 2018 NeuroReceptor Mapping conference, the brain PET community was challenged with a computational contest involving a simulated neurotransmitter release experiment. Fourteen international teams analysed the same imaging dataset, for which the ground-truth was known. Despite a plurality of methods, the solutions were consistent across participants, although not identical. These results should create awareness that the increased sharing of PET data alone will only be one component of enhancing confidence in neuroimaging results and that it will be important to complement this with full details of the analysis pipelines and procedures that have been used to quantify data.

The cerebral cholinergic system is involved in several cognitive processes and neuropsychiatric 2 diseases. For research purposes and later on in routine clinical settings new PET radioligands with more favorable characteristics than the established 3-pyridylether derivatives with their slow kinetics are necessary. Here we present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)-targeting radioligand (+)-[18F]Flubatine. Primary aim of this study was to develop a kinetic modeling-based approach to quantify the α4β2 nAChR availability in the human brain and to compare respective data of healthy controls (HCs) with those of patients with Alzheimer’s disease (AD). Secondary aims were to investigate whether (+)-[18F]Flubatine binding was correlated to cognitive test data or β-amyloid radiotracer accumulation. Furthermore, the partial volume effect (PVE) on regional (+)-[18F]Flubatine binding was investigated. We examined 11 non-smoking HCs and 9 non-smoking patients with mild AD without anti-dementive drugs. Prior to (+)-[18F]Flubatine PET, all subjects underwent an extensive neuropsychological testing and a β-amyloid [11C]PiB PET/MRI examination. To evaluate the (+)-[18F]Flubatine PET data, we used full kinetic modeling (one and two tissue compartment 16 modeling (1TCM and 2TCM)) and regional as well as voxel-based analyses. 270 min p.i., the unchanged parent compound in arterial blood amounted to 97±2%. As revealed by regional analysis, (+)-[18F]Flubatine distribution volume (binding) was significantly reduced in the bilateral mesial temporal cortex in AD patients compared to HCs (right: AD: 10.6±1.1 vs HC: 11.6±1.4, p=0.049; left: AD: 11.0±1.1 vs HCs:12.2±1.8, p=0.046). Voxel-based analysis detected further clusters of reduced (+)-[18F]Flubatine in left precuneus/posterior cingulate cortex, right superior temporal and left middle temporal cortex (k>30, p0.5, p

Purpose: Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD. Methods: Using [18F] fluspidine PET (300 MBq, 0–90 min), 11 male HVs (pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (pridopidine 90 mg) were investigated twice, without and 2 h after single dose of pridopidine. Using [18F] fallypride PET (200 MBq, 0–210 min), four male HVs were studied without and 2 h following pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot. Results: S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%). Conclusions: Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine’s mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41. © 2020, The Author(s).

Introduction Electrical gastric vagus nerve stimulation (VNS) shifts the sympathetic-vagal balance toward a parasympathetic predominance (1). We aim to assess central changes in α7 nAChR-mediated transmission and hypothesize that VNS changes the parasympathetic tone by changing the α7 nAChR availability in the nucleus tractus solitarii (NTS) and distinct cortical and subcortical regions (2). Material and Methods Following a standard 35-frames, 120-min protocol for dynamic brain PET imaging, data from eight piglets (15.6 ± 3.2 kg, ~6 weeks) were acquired post injection of 194.8 ± 9.4 MBq of [18F]DBT-10 (3) followed by T1-MPRAGE MRI: three baseline, two with infusion of the acetylcholine esterase inhibitor physostigmine (0.04 mg/kg, 1 ml/min, at 10 min prior to tracer injection; 0.24 mg/kg, 1 ml/min, at tracer injection/scan start over 120 min) and three with VNS in repeated sequences of 0.5 Hz over 5 min, 5 min pause started at scan start. TACs were analyzed using a 2-tissue compartment model involving a metabolite-corrected arterial input function to generate individual total distribution volumes (VT) as receptor parameter. Results Compared to baseline, we observed an increase of the mean VT after physostigmine infusion (61 %) as well as after VNS (28 %) without major alterations of K1 in the NTS (Figure 1 and 2). Conclusion These initial data indicate blood-flow-independent changes under VNS as compared with baseline suggesting an increase in α7 nAChR availability although the changes appear more heterogeneous in VNS as compared with physostigmine. The finding is in contrast to our hypothesis expecting lower α7 nAChR-availability as a result of increased acetylcholine release following VNS. We speculate that higher VT under VNS may reflect an increase in affinity of the α7 nAChR or result in an upregulation of the α7 nAChR. Increase of VT following physostigmine administration could be related to a positive allosteric effect on the α7 nAChR. Furthermore, the results of this study allow sample size estimations for further preclinical and clinical studies.