(+)-[(18)F]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

PURPOSES: We present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)–targeting radioligand (+)-[(18)F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[(18)F]Flubatine and compare the data of healthy controls (HCs) and patients with Alzheimer’s disease (AD); to investigate the partial volume effect (PVE) on regional (+)-[(18)F]Flubatine binding; and whether (+)-[(18)F]Flubatine binding and cognitive test data respective β-amyloid radiotracer accumulation were correlated. METHODS: We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [(11)C]PiB PET/MRI examination. (+)-[(18)F]Flubatine PET data were evaluated using full kinetic modeling and regional as well as voxel-based analyses. RESULTS: With 270-min p.i., the unchanged parent compound amounted to 97 ± 2%. Adequate fits of the time-activity curves were obtained with the 1 tissue compartment model (1TCM). (+)-[(18)F]Flubatine distribution volume (binding) was significantly reduced in bilateral mesial temporal cortex in AD patients compared with HCs (right 10.6 ± 1.1 vs 11.6 ± 1.4, p = 0.049; left 11.0 ± 1.1 vs 12.2 ± 1.8, p = 0.046; one-sided t tests each). PVE correction increased not only (+)-[(18)F]Flubatine binding of approximately 15% but also standard deviation of 0.4–70%. Cognitive test data and (+)-[(18)F]Flubatine binding were significantly correlated in the left anterior cingulate, right posterior cingulate, and right parietal cortex (r > 0.5, p < 0.05 each). In AD patients, (+)-[(18)F]Flubatine binding and [(11)C]PiB standardized uptake value ratios were negatively correlated in several regions; whereas in HCs, a positive correlation between cortical (+)-[(18)F]Flubatine binding and [(11)C]PiB accumulation in the white matter was found. No adverse event related to (+)-[(18)F]Flubatine occurred. CONCLUSION: (+)-[(18)F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[(18)F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[(18)F]Flubatine binding indicated an association between white matter integrity and availability of α4β2 nAChRs. Overall, (+)-[(18)F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4β2 nAChR–targeting PET ligand in further clinical trials. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00259-020-05029-w) contains supplementary material, which is available to authorized users.