(+)-[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.

Abstract

We present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)-targeting radioligand (+)-[¹⁸F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[¹⁸F]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 (+)-[¹⁸F]Flubatine binding; and whether (+)-[¹⁸F]Flubatine binding and cognitive test data respective β-amyloid radiotracer accumulation were correlated. We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [¹¹C]PiB PET/MRI examination. (+)-[¹⁸F]Flubatine PET data were evaluated using full kinetic modeling and regional as well as voxel-based analyses. 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). (+)-[¹⁸F]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 (+)-[¹⁸F]Flubatine binding of approximately 15% but also standard deviation of 0.4-70%. Cognitive test data and (+)-[¹⁸F]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, (+)-[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 adverse event related to (+)-[¹⁸F]Flubatine occurred. (+)-[¹⁸F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[¹⁸F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[¹⁸F]Flubatine binding indicated an association 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.