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. Conclusion: 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%.

Radiation dosimetry of the α4β2 nicotinic receptor ligand (+)-[18F]flubatine, comparing preclinical PET/MRI and PET/CT to first-in-human PET/CT results

“…Furthermore, we demonstrated the feasibility of small animal PET/MR imaging to estimate the radiation dose in humans based on mice biokinetic image data scaled to human anatomy. However, the presented study confirmed that preclinical internal dosimetry underestimates the ED in humans by 38–47 % as it has already been shown for (−)-[ 18 F]flubatine [ 16 ] and other radiotracers [ 37 – 40 ].…”

“…The activity data of each VOI was assigned to the individual organ or tissue and subsequently transformed into percentage of injected dose (%ID organ ) with Eq. 1 [ 16 ], …”

“…The enantiomers (−)-[ 18 F]flubatine and (+)-[ 18 F]flubatine have a high affinity (Ki = 0.112 nM, Ki = 0.064 nM, respectively) and selectivity [ 12 ] to α 4 β 2 receptors as demonstrated in mice [ 12 ], piglets [ 13 ], and rhesus monkeys [ 14 ]. Although both enantiomers are suitable for clinical application, the (−) enantiomer was chosen first due to faster binding kinetics in pig brains [ 15 ] for an early clinical study [ 16 ]. As expected, (−)-[ 18 F]flubatine showed fast kinetics in humans reaching its pseudo equilibrium within 90 min p.i.…”

“…injection of (+)-[ 18 F]flubatine in mice, piglets, and humans, as presented in this work, to previous dosimetry data of an ex vivo biodistribution study (organ harvesting method) in 27 mice and PET/CT imaging of 6 piglets and 3 humans after i.v. injection of (−)-[ 18 F]flubatine [ 16 ].…”

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

“…48 The first fully automated radiosynthesis of this compound validated for human use 49 was reported in 2013 and first-in-human results of administration of the radiotracer showed no adverse effects in humans. 50 Tracer binding to plasma proteins in human blood was demonstrated in vitro and ex vivo to show no differences between patients with Alzheimer’s disease and healthy controls. 51 [ 11 C]CHIBA-1001 is a PET radiotracer for the α-7 subtype of nAChR.…”