title: Internal dose assessment of (-)-18F-flubatine, comparing animal model datasets of mice and piglets with first-in-human results.
abstract: (-)-(18)F-flubatine is a promising tracer for neuroimaging of nicotinic acetylcholine receptors (nAChRs), subtype α4β2, using PET. Radiation doses after intravenous administration of the tracer in mice and piglets were assessed to determine the organ doses (ODs) and the effective dose (ED) to humans. The results were compared with subsequent clinical investigations in human volunteers.
  
  
  METHODS
  Twenty-seven female CD1 mice (weight ± SD, 28.2 ± 2.1 g) received intravenous injection of 0.75 ± 0.33 MBq of (-)-(18)F-flubatine. Up to 240 min after injection, 3 animals per time point were sacrificed and the organs harvested, weighed, and counted in a γ counter to determine mass and activity, respectively. Furthermore, whole-body PET scans of 5 female piglets (age ± SD, 44 ± 3 d; weight ± SD, 13.7 ± 1.7 kg) and 3 humans (2 men and 1 woman; age ± SD, 59.6 ± 3.9 y; weight ± SD, 74.3 ± 3.1 kg) were obtained up to 236 min (piglets) and 355 min (humans) after injection of 186.6 ± 7.4 and 353.7 ± 10.2 MBq of (-)-(18)F-flubatine, respectively, using a PET/CT scanner. The CT was used for delineation of the organs. Exponential curves were fitted to the time-activity-data, and time and mass scales were adapted to the human anatomy. The ODs were calculated using OLINDA/EXM (version 1.0); EDs were calculated with the tissue-weighting factors of ICRP103.
  
  
  RESULTS
  After the injection of (-)-(18)F-flubatine, there were no adverse or clinically detectable pharmacologic effects in any of the subjects. The highest activities after injection were found in the kidneys, urinary bladder, and liver. The urinary bladder receives the highest OD in all investigated species, followed by the kidneys and the liver for animals and humans, respectively. On the basis of mouse, piglet, and human kinetic data, the projected human ED of (-)-(18)F-flubatine was estimated to be 12.5 μSv/MBq in mice, 14.7 ± 0.7 μSv/MBq in piglets, and 23.4 ± 0.4 μSv/MBq in humans.
  
  
  CONCLUSIONS
  As has been demonstrated for other PET radiotracers, preclinical (i.e., animal-derived) dosimetry underestimates the ED to humans, in the current case of (-)-(18)F-flubatine by 34%-44%.
authors.affiliation: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany bernhard.sattler@medizin.uni-leipzig.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Sattler
authors.affiliation: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, Dresden/Leipzig, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Kranz
authors.affiliation: Department of Nuclear Medicine, Diaconal Hospital Henriettenstiftung Hannover, Hannover, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Starke
authors.affiliation: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wilke
authors.affiliation: Department of Nuclear Medicine, Diaconal Hospital Henriettenstiftung Hannover, Hannover, Germany.
authors.forename: Cornelius K
authors.initials: CK
authors.lastname: Donat
authors.affiliation: Department of Nuclear Medicine, Diaconal Hospital Henriettenstiftung Hannover, Hannover, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Patt
authors.affiliation: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schildan
authors.affiliation: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Patt
authors.affiliation: ABX Advanced Biochemical Compounds Ltd., Radeberg, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Smits
authors.affiliation: ABX Advanced Biochemical Compounds Ltd., Radeberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoepping
authors.affiliation: Department of Psychiatry, University Hospital Leipzig, Leipzig, Germany; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Schoenknecht
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: Department of Nuclear Medicine, Diaconal Hospital Henriettenstiftung Hannover, Hannover, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.affiliation: Department of Nuclear Medicine, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Osama
authors.initials: O
authors.lastname: Sabri
mesh_terms: D000818:Animals; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002138:Calibration; D016208:Databases, Factual; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D064847:Multimodal Imaging; D049268:Positron-Emission Tomography; D011829:Radiation Dosage; D011874:Radiometry / Q000379:methods*; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic / Q000737:chemistry; D013552:Swine; D014018:Tissue Distribution; D001743:Urinary Bladder / Q000000981:diagnostic imaging; D051598:Whole Body Imaging
chemical_list: D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; C115362:fluoronorchloroepibatidine
keywords: (−)-18F-flubatine; nicotinic receptors; positron emission tomography; radiation dosimetry; α4β2