Radiation Dosimetry of a Novel Adenosine A2A Receptor Radioligand [11C]Preladenant Based on PET/CT Imaging and Ex Vivo Biodistribution in Rats

Molecular Imaging and Biology, Aug 2016

Purpose [11C]Preladenant was developed as a novel adenosine A2A receptor PET radioligand. The aim of this study was to determine the radiation dosimetry of [11C]preladenant and to investigate whether dosimetry estimation based on organ harvesting can be replaced by positron emission tomography (PET)/x-ray computed tomography (CT) imaging in rats. Procedures Male Wistar rats (n = 35) were i.v. injected with [11C]preladenant. The tracer biodistribution was determined by organ harvesting at 1, 5, 15, 30, 60, and 90 min post injection. Hollow organs including the stomach, intestines, and urinary bladder were harvested with contents. In 10 rats, a 90-min dynamic PET/CT scan of the torso was acquired. Twenty volumes of interest (VOIs) were manually drawn on the PET image using the CT image of the same animal as anatomical reference. The dynamic time-activity curves were used to calculate organ residence times (RTs). Human radiation dosimetry estimates, derived from rat data, were calculated with OLINDA/EXM 1.1. Results PET-imaging and organ-harvesting estimated comparable organ RTs, with differences of 6–27 %, except for the lungs, pancreas, and urinary bladder, with differences of 48, 53, and 60, respectively. The critical organ was the small intestine with a dose of 25 μSv/MBq. The effective doses (EDs) calculated from imaging-based and organ-harvesting-derived data were 5.5 and 5.6 μSv/MBq, respectively, using the International Commission on Radiological Protection 60 tissue weighting factors. Conclusions The ED of [11C]preladenant (2 mSv for a 370-MBq injected dose) is comparable with other C-11-labeled PET tracers. Estimation of the radiation dosimetry of [11C]preladenant by PET/CT imaging in rats is feasible and gives comparable results to organ harvesting, provided that small VOIs are used and the content of hollow organs is taken into account. Dosimetry by PET imaging can strongly reduce the number of laboratory animals required.

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Radiation Dosimetry of a Novel Adenosine A2A Receptor Radioligand [11C]Preladenant Based on PET/CT Imaging and Ex Vivo Biodistribution in Rats

Radiation Dosimetry of a Novel Adenosine A2A 11 Receptor Radioligand [ C]Preladenant Based on PET/CT Imaging and Ex Vivo Biodistribution in Rats Xiaoyun Zhou 0 Philip H. Elsinga 0 Shivashankar Khanapur 0 Rudi A. J. O. Dierckx 0 Erik F. J. de Vries 0 Johan R. de Jong 0 0 Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen , Groningen , The Netherlands Purpose: [11C]Preladenant was developed as a novel adenosine A2A receptor PET radioligand. The aim of this study was to determine the radiation dosimetry of [11C]preladenant and to investigate whether dosimetry estimation based on organ harvesting can be replaced by positron emission tomography (PET)/x-ray computed tomography (CT) imaging in rats. Procedures: Male Wistar rats (n = 35) were i.v. injected with [11C]preladenant. The tracer biodistribution was determined by organ harvesting at 1, 5, 15, 30, 60, and 90 min post injection. Hollow organs including the stomach, intestines, and urinary bladder were harvested with contents. In 10 rats, a 90-min dynamic PET/CT scan of the torso was acquired. Twenty volumes of interest (VOIs) were manually drawn on the PET image using the CT image of the same animal as anatomical reference. The dynamic time-activity curves were used to calculate organ residence times (RTs). Human radiation dosimetry estimates, derived from rat data, were calculated with OLINDA/EXM 1.1. Results: PET-imaging and organ-harvesting estimated comparable organ RTs, with differences of 6-27 %, except for the lungs, pancreas, and urinary bladder, with differences of 48, 53, and 60, respectively. The critical organ was the small intestine with a dose of 25 μSv/MBq. The effective doses (EDs) calculated from imaging-based and organ-harvesting-derived data were 5.5 and 5.6 μSv/MBq, respectively, using the International Commission on Radiological Protection 60 tissue weighting factors. Conclusions: The ED of [11C]preladenant (2 mSv for a 370-MBq injected dose) is comparable with other C-11-labeled PET tracers. Estimation of the radiation dosimetry of [11C]preladenant by PET/CT imaging in rats is feasible and gives comparable results to organ harvesting, provided that small VOIs are used and the content of hollow organs is taken into account. Dosimetry by PET imaging can strongly reduce the number of laboratory animals required. Radiation dosimetry; [11C]preladenant; Small-animal PET/CT; Adenosine A2A receptor; Rat Introduction The adenosine A2A receptor (A2AR) has been studied as a potential therapeutic target in peripheral inflammatory diseases [ 1 ] and in brain disorders, such as depression [ 2 ], drug addiction [ 3 ], Alzheimer’s disease [ 4 ], and Parkinson’s disease [ 5 ]. We have recently synthesized [11C]preladenant, a novel positron emission tomography (PET) radioligand for the imaging of A2AR in the central nervous system [ 6 ]. The tracer displayed excellent target-to-non-target ratios as well as favourable pharmacokinetic profiles, which warrants its translation to studies in human subjects. Before performing a clinical study, a radiation dosimetry estimation is necessary to determine the dose limit of a new radiopharmaceutical [ 7 ]. Experimental animals have been used to estimate the radiation burden of a new tracer in humans. Preclinical radiation dosimetry measurements are often performed in non-human primates with PET imaging, and in rodents with organ harvesting at several time points post injection [ 8–10 ]. Due to the influence of the animal rights movement, studies on non-human primates are subject of discussion, while conventional ex vivo organ dissection in rodents requires a large number of animals (i.e., 24 animals for a typical ex vivo biodistribution study) to obtain the dynamic biodistribution data of radiopharmaceuticals required for dosimetry calculations. With the improvement of spatial resolution of the PET camera, small-animal PET imaging emerges as a promising alternative to study tracer distribution in vivo [ 11–14 ]. Dynamic PET-imaging enables studying tracer biodistribution over time using a single animal with much higher time resolution compared with organ-harvesting. The first dosimetry study with PET imaging in rodents was reported by Palm et al. [15], using Y-86 Trastuzumab to estimate the absorbed doses of [90Y]Trastuzumab in tumor and several organs in tumorbearing nude mice. Absorbed doses in mice were calculated following the Medical Internal Radiation Dose (MIRD) method, using the murine-specific S factors. However, dynamic PET imaging data from previous studies showed significant deviation from organ harvesting in multiple organs, probably due to the small organ sizes comparative to the low spatial resolution of the PET camera, resulting in a severe partial volume effect (PVE)/spillover effect on imaging data. Moreover, due to loss of contents of hollow organs during the organ dissection, large discrepancies were found (...truncated)


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Xiaoyun Zhou, Philip H. Elsinga, Shivashankar Khanapur, Rudi A. J. O. Dierckx, Erik F. J. de Vries, Johan R. de Jong. Radiation Dosimetry of a Novel Adenosine A2A Receptor Radioligand [11C]Preladenant Based on PET/CT Imaging and Ex Vivo Biodistribution in Rats, Molecular Imaging and Biology, 2017, pp. 289-297, Volume 19, Issue 2, DOI: 10.1007/s11307-016-0992-3