Distribution of the P2X7-receptor-targeted [11C]GSK1482160 radiopharmaceutical in normal human subjects

1009 Objectives: [11C]GSK14821601,2 is a high affinity ligand (Kd = 1.15 ± 0.12 nM)3 for the human P2X7 receptor, which is highly expressed by activated cells of the immune system. This study was undertaken to determine the distribution and pharmacokinetics of [11C]GSK1482160 in normal human volunteers, in order to estimate radiopharmaceutical radiation dosimetry. Methods. Following a protocol approved by the Indiana University IRB, [11C]GSK1482160 was intravenously administered to 10 normal volunteers (5 male, 5 female; 33 ± 12 years old, range 21-57 years, median 26.5 years; male body mass 76.4 ± 7.5 kg, female body mass 60.9 ± 9.2 kg). The administered dose was 26 ± 2 mCi (966 ± 75 MBq). At injection, the molar activity was 1.03 ± 0.28 mCi/nmol (38.1 ± 10.4 MBq/nmol). The radiopharmaceutical was injected with a segment of the left ventricle, and the top of one kidney, in the field-of-view of a Siemens mCT camera for a 6-minute list-mode acquisition. Subsequently, twelve or thirteen serial whole-body images (thigh-head) were collected using the Siemens Flow-Motion acquisition software. The timing of the sequential continuous motion whole-body scans was approximately 4 x 2-minutes; 3 x 4-minutes; 3 x 5.5-minutes, and 3 x 8-minutes (exact timing varied slightly with subject height). Radiation dosimetry was estimated using OLINDA after extracting tissue cumulative activity data from the PET images. Results. The [11C]GSK1482160 radiopharmaceutical showed rapid first-pass blood clearance following bolus intravenous administration, with a subsequent blood half-time of 39 ± 8 minutes. As expected, [11C]GSK1482160 is lipophilic, with a measured octanol/water partition coefficient logP = 1.95 ± 0.01 (n = 4). Consistent with this lipophilicity, liver uptake dominates the whole-body [11C]GSK1482160 images. Brain and urine accumulation of 11C at 20-minutes post injection gave average SUV values of 1.04 ± 0.19 and 7.21 ± 6.57 respectively. The brain uptake corresponds to approximately 2% of the injected dose. Data from the male subjects gave estimated radiation exposures of 0.13, 0.091, and 0.068 rem/mCi (0.035, 0.025, and 0.018 mSv/MBq) to the urinary bladder wall, liver, and kidneys, respectively. Data from the female subjects gave estimated radiation exposures of 0.17, 0.14, and 0.082 rem/mCi (0.045, 0.038, and 0.022 mSv/MBq) to the urinary bladder wall, liver, and kidneys, respectively. Conclusions: Brain uptake was low, but in most other organs the uptake and clearance of [11C]GSK1482160 appears suitable for use in PET assessment of P2X7 receptor expression as a potential marker of regional inflammation. Supported by the Renal Imaging Technology Development Program of the IUPUI Research Center for Quantitative Renal Imaging, and the Indiana University Department of Radiology and Imaging Sciences. Research reported in this publication was also partially supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA202695. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.