title: Radiation dosimetry of the α4β2nicotinic receptor ligand (+)-[18F]flubatine, comparing preclinical PET/MRI and PET/CT to first-in-human PET/CT results.
abstract: BACKGROUND
  Both enantiomers of [18F]flubatine are new radioligands for neuroimaging of α4β2nicotinic acetylcholine receptors with positron emission tomography (PET) exhibiting promising pharmacokinetics which makes them attractive for different clinical questions. In a previous preclinical study, the main advantage of (+)-[18F]flubatine compared to (-)-[18F]flubatine was its higher binding affinity suggesting that (+)-[18F]flubatine might be able to detect also slight reductions of α4β2nAChRs and could be more sensitive than (-)-[18F]flubatine in early stages of Alzheimer's disease. To support the clinical translation, we investigated a fully image-based internal dosimetry approach for (+)-[18F]flubatine, comparing mouse data collected on a preclinical PET/MRI system to piglet and first-in-human data acquired on a clinical PET/CT system. Time-activity curves (TACs) were obtained from the three species, the animal data extrapolated to human scale, exponentially fitted and the organ doses (OD), and effective dose (ED) calculated with OLINDA.
  
  
  RESULTS
  The excreting organs (urinary bladder, kidneys, and liver) receive the highest organ doses in all species. Hence, a renal/hepatobiliary excretion pathway can be assumed. In addition, the ED conversion factors of 12.1 μSv/MBq (mice), 14.3 μSv/MBq (piglets), and 23.0 μSv/MBq (humans) were calculated which are well within the order of magnitude as known from other18F-labeled radiotracers.
  
  
  CONCLUSIONS
  Although both enantiomers of [18F]flubatine exhibit different binding kinetics in the brain due to the respective affinities, the effective dose revealed no enantiomer-specific differences among the investigated species. The preclinical dosimetry and biodistribution of (+)-[18F]flubatine was shown and the feasibility of a dose assessment based on image data acquired on a small animal PET/MR and a clinical PET/CT was demonstrated. Additionally, the first-in-human study confirmed the tolerability of the radiation risk of (+)-[18F]flubatine imaging which is well within the range as caused by other18F-labeled tracers. However, as shown in previous studies, the ED in humans is underestimated by up to 50 % using preclinical imaging for internal dosimetry. This fact needs to be considered when applying for first-in-human studies based on preclinical biokinetic data scaled to human anatomy.
authors: Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany.
authors: Mathias
authors: M
authors: Kranz
authors: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
authors: Bernhard
authors: B
authors: Sattler
authors: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
authors: Solveig
authors: S
authors: Tiepolt
authors: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
authors: Stephan
authors: S
authors: Wilke
authors: Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany.
authors: Winnie
authors: W
authors: Deuther-Conrad
authors: Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany.|Division of Brain Sciences, Department of Medicine, Hammersmith Hospital Campus, Imperial College London, London, UK.
authors: Cornelius K
authors: CK
authors: Donat
authors: Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany.
authors: Steffen
authors: S
authors: Fischer
authors: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
authors: Marianne
authors: M
authors: Patt
authors: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
authors: Andreas
authors: A
authors: Schildan
authors: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
authors: Jörg
authors: J
authors: Patt
authors: ABX advanced biochemical compounds Ltd., Radeberg, Germany.
authors: René
authors: R
authors: Smits
authors: ABX advanced biochemical compounds Ltd., Radeberg, Germany.
authors: Alexander
authors: A
authors: Hoepping
authors: Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany.
authors: Jörg
authors: J
authors: Steinbach
authors: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
authors: Osama
authors: O
authors: Sabri
authors: Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany. p.brust@hzdr.de.
authors: Peter
authors: http://orcid.org/0000-0001-5555-7058
authors: P
authors: Brust
keywords: (+)-[18F]flubatine; Dosimetry; Image-based internal dosimetry; Nicotinic receptors; OLINDA/EXM; Preclinical hybrid PET/MRI; Radiation safety