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(+)-[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.

  • Tiepolt, Solveig1
  • Becker, Georg-Alexander2
  • Wilke, Stephan2
  • Cecchin, Diego3
  • Rullmann, Michael2
  • Meyer, Philipp M2
  • Barthel, Henryk2
  • Hesse, Swen2
  • Patt, Marianne2
  • Luthardt, Julia2
  • Wagenknecht, Gudrun4
  • Sattler, Bernhard2
  • Deuther-Conrad, Winnie5
  • Ludwig, Friedrich-Alexander5
  • Fischer, Steffen5
  • Gertz, Hermann-Josef6
  • Smits, René7
  • Hoepping, Alexander7
  • Steinbach, Jörg8
  • Brust, Peter5
  • And 1 more
  • 1 Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany. [email protected] , (Germany)
  • 2 Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany. , (Germany)
  • 3 Department of Medicine, University-Hospital of Padova, Via Giustiniani 2, 35128, Padova, Italy. , (Italy)
  • 4 Electronic Systems (ZEA-2), Central Institute for Engineering, Electronics and Analytics, Research Centre Juelich, Wilhelm-Johnen-Straße, 52428, Juelich, Germany. , (Germany)
  • 5 Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstraße 15, 04318, Leipzig, Germany. , (Germany)
  • 6 Department of Psychiatry, University of Leipzig, Semmelweisstraße 10, 04103, Leipzig, Germany. , (Germany)
  • 7 ABX advanced biochemical compounds GmbH, Heinrich-Gläser-Straße 10, 01454, Radeberg, Germany. , (Germany)
  • 8 Helmholtz-Zentrum Dresden-Rossendorf, Bautzener Landstr. 400, 01328, Dresden, Germany. , (Germany)
Published Article
European Journal of Nuclear Medicine
Publication Date
Mar 01, 2021
DOI: 10.1007/s00259-020-05029-w
PMID: 32935187


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.

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