Biodistribution, radiodosimetry and pharmacokinetics of [18F]GSK1482160 for cerebral P2X7 receptor in living subjects

Increasing evidence of the role of neuroinflammation in pathophysiology has highlighted the importance of P2X7 receptor (P2X7R)-targeted neurodegeneration diseases. The safety, biodistribution, pharmacokinetics and dosimetry of a promising F-18-labeled PET tracer [18F]GSK1482160 for imaging P2X7R were evaluated. The absorbed dose (AD) and effective dose (ED) of nonhuman primates (NHPs) and human adult volunteers were estimated. The total volume distribution (VT) was calculated via the 2-tissue compartment model (2TCM) and Logan plot (LoganAIF). There were no adverse events after [18F]GSK1482160 dosing. Radioactivity accumulated predominantly in the hepatobiliary system, kidney, spleen, and brain. Organ dosimetry revealed the liver as the critical organ with a mean AD of 30.1 µGy/MBq, followed the adrenals at 22.8 µGy/MBq. The overall ED of the female and male human volunteers were 10.9 µSv/MBq and 8.88 µSv/MBq, respectively. [18F]GSK1482160 has the ability to cross the blood–brain barrier and is distributed throughout the whole brain with low region specificity. The 2TCM and LoganAIF models had good correlation and agreement, and the input functions of the image-derived and blood-sampling methods had good correlation but poor correspondence. The AD and ED produced by [18F]GSK1482160 were within typical levels for fluorine-18-labeled tracers. [18F]GSK1482160 is a safe PET tracer with hepatorenal metabolism and it is up to 250 MBq (6.7 mCi) for human adults of [18F]GSK1482160 can be administered of a total effective dose of 2.73 mSv (0.273 rem) with the critical organ, the liver, receiving the maximum allowed exposure of 50 mSv (5 rem) in accordance with ICRP 103 recommendations. 2TCM and LoganAIF using a blood-sampling input function with blood metabolite correction are accurate methods for quantifying the tracer binding of P2X7R in the brain.