(+)-[18F]Flubatine as a novel α4β2 nicotinic acetylcholine receptor PET ligand – Results of the first-in-human brain imaging application in patients with β-amyloid PET-confirmed Alzheimer’s disease and healthy controls

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, p<0.001). PVE correction revealed an increase of regional (+)-[18F]Flubatine binding of approximately 15% but also an increase of the standard deviation of 0.4-70% resulting in a loss of statistical significances. Thus, we also estimated the cortical thickness to investigate whether cortical atrophy significantly affects the regional (+)-[18F]Flubatine binding. Here, we found that mesial temporal cortical thickness did not correlate with (+)-[18F]Flubatine binding (right: r=0.10, p=0.69; left: r=0.17, p=0.48). Using a reference region (occipital cortex), also the right parietal cortex showed reduced relative (+)-[18F]Flubatine binding in AD patients compared to HCs (1.1±0.1 vs. 1.2±0.1, p=0.033). Cognitive test data and (+)-[18F]Flubatine binding were significantly correlated in left anterior cingulate cortex, right posterior cingulate cortex and right parietal cortex (r>0.5, p<0.05 each). In the AD patients, (+)-[18F]Flubatine binding and [11C]PiB standardized uptake value ratios were negatively correlated in several regions, whereas in HCs a positive correlation between cortical (+)-[18F]Flubatine binding and [11C]PiB accumulation in the white matter was found. No serious adverse events were registered, and seven adverse events which were not related to the investigational product. Taken together, (+)-[18F]Flubatine is a safe and stable PET ligand. Full kinetic modeling of the PET data can be realized by 1TCM without metabolite correction. (+)-[18F]Flubatine binding affinity was high enough to detect group differences without the use of a reference region. However, the use of the occipital cortex as reference region increased the sensitivity. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[18F]Flubatine binding indicated a connection between white matter integrity and availability of α4β2 nAChRs. Overall, (+)-[18F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4β2 nAChR-targeting PET ligand in further clinical trials.