Dosimetry of preclinical and clinical case studies of 18F-radiopharmaceuticals using Positron Emission Tomography and Computed Tomography: Methods of quantification, their improvement and considerations of critical exposures

Computed tomography (CT) and positron emission tomography (PET) are routinely used in (pre)clinical research and practice. The radiation burden inflicted on subjects from both modalities needs to be addressed to keep exposures as low as possible. While the focus in literature is on human dosimetry, few studies investigate the animal dosimetry in preclinical studies. This doctoral thesis aimed to quantify the radiation burden imposed on subjects by CT and PET in clinical and especially preclinical case studies using both experimental data and Monte Carlo simulations. We derived the biodistribution of three 18F-radiopharmaceuticals (18F-UCB-H, 6-[18F]fluoro-L-DOPA and 2-[18F]fluoro-L-Tyrosine) in mice using the gold standard method organ harvesting, as well as dynamic microPET imaging and the new technique of hybrid imaging, where microPET activities are cross-calibrated with the activity remaining in post-scan harvested organs. The radiation dosimetry in humans was calculated and results of all methods were compared. For the newly developed tracer 18F-UCB-H, a first-in-human clinical study was conducted and the radiation dosimetry was compared to preclinically obtained data. Additionally, the preclinically obtained human dosimetry of 6-[18F]fluoro-L-DOPA was compared to clinical values available in the literature. The derived biodistributions of the three tracers were also applied to mouse S-factors to calculate absorbed doses in mice. Furthermore, the radiation dosimetry of the small animal microCT GE eXplore 120 was experimentally investigated ex vivo in a custom built phantom and in vivo in rats. A model of the imaging system was built using Monte Carlo simulations to further investigate the radiation dosimetry non-invasively. The preclinical study of the three 18F-radiopharmaceuticals in mice showed that hybrid imaging produces equivalent results compared to labour intensive organ harvesting while being more efficient from an ethical, economical, and scientific point of view. Sole dynamic microPET imaging produced poor results due to partial volume effects and quantification errors in small volumes. Clinically and preclinically derived data of 18F-UCB-H and 6-[18F]fluoro-L-DOPA agreed roughly regarding total body absorbed dose and effective dose, but significant differences were revealed in organ absorbed doses for both tracers. The experimentally derived radiation dosimetry of microPET and microCT imaging in mice showed that animals are exposed to significant amounts of radiation in preclinical studies. Monte Carlo simulations of the GE eXplore 120 were in good agreement with experimental results and provided a deeper insight into the spatial dose distribution. Based on our analysis, hybrid imaging could serve as a replacement for the current gold standard of organ harvesting in preclinical dosimetry. Preclinically obtained estimates of human dosimetry showed relatively poor accuracy and should be used with caution for the calculation of injection limits in first-in-human studies. We demonstrated that excessive radiation doses are inflicted on small animals in preclinical imaging, especially in dual-modality longitudinal studies. The radiation should be addressed in advance to avoid critical exposures that might compromise the outcome of the study