Abstract
1014
Aim: The A2AR has emerged as promising target for the treatment of Parkinson’s disease (PD). In the central nervous system, the A2AR is abundantly expressed in the basal ganglia with the highest expression in the striatum. Treatment with A2AR antagonists potentially can improve the mobility of PD patients in early stages1 as well as potentially reduce the adverse effects of long term L-DOPA treatment2,3. In this study, the organ equivalent doses (OD) and the effective dose (ED) of [18F]FLUDA, a promising radioligand for A2AR imaging with PET, were estimated in juvenile pigs to prepare this radiotracer for clinical translation. Method: Whole body dosimetry was performed in 3 male piglets (age: ~6 weeks, weight: ~13-15 kg) The animals were anesthetized and investigated by sequential PET imaging up to 5h post i.v. injection of ~120 MBq [18F]FLUDA on a SIEMENS Biograph16 PET/CT-system with 7 bed positions (BP) per frame, 1.5 to 6 min/BP, CT-attenuation correction and iterative reconstruction. All relevant organs were defined by volumes of interest. Exponential curves were fitted to the time-activity-data (% ID/g, and % ID/organ). Time- and mass-scales were adapted to their human orders of magnitude. The ODs were calculated using the ICRP 89 adult male phantom with OLINDA version 2.1. The ED was calculated using tissue weighting factors as published in the ICRP103.
Results: The highest ODs were received by the pancreas (178.0µSv/MBq), the liver and the kidneys (66.0 and 64.1µSv/MBq, respectively), the spleen, urinary bladder wall and adrenals (49.3, 40.6 and 26.2µSv/MBq, respectively). The highest contribution to the ED was by the liver and the stomach wall (2.6µSv/MBq each), the pancreas and the urinary bladder wall (1.6µSv/MBq each) and the lungs (1.2µSv/MBq). According to this data, the ED to humans is 16.4 µSv/MBq. Conclusion: Taking into account that preclinical dosimetry underestimates the dose to humans by up to 40%4, the ED upon i.v. application of about 300 MBq [18F]FLUDA to humans would be 8.2 mSv. This is well within the range of what other 18F-labeled compounds cause to humans. This risk assessment encourages to transfer [18F]FLUDA to clinical study phases to further investigate its potential as a clinical tool for therapy monitoring in PD with PET. References: 1Pinna, A et al. CNS Drugs 2014, 28, 455-74 2Cieslak, M et al. Purinergic Signal 2008, 4, 305-12 3Fuxe, K et al. Mov Disord 2007, 22, 1990-2017 4Sattler, B et al. J Nucl Med 2014, 55[11], 1885-92