Introduction: A number of substrate for P-glycoprotein (Pgp), such as (R)-[11C]verapamil ([11C]VER), has been developed for imaging P-gp function with positron emission tomography (PET). These substrates have high affinity for P-gp and can measure decreased function which results in an increased tracer brain uptake. However, it is not possible to measure over-expression of P-gp function, because the concentration of the tracer at baseline is already extremely low. Recently developed [18F]MC225 is a selective substrate for P-gp with a good metabolic stability and showed higher baseline uptake than that of other P-gp substrates. In addition, [18F]MC225 is a weaker P-gp substrate than [11C]VER. These properties would be suitable for measuring over-expression of P-gp in the brain, which is associated with drug resistance e.g. in case of epilepsy and depression. For clinical application in humans, direct comparison using both tracers in the non-human primate was conducted. Subjects and Methods: A total of 12 PET measurements with [11C]VER and [18F]MC225 under baseline and blocking conditions were performed in 3 conscious state male monkeys (Macaca mulatta) with arterial blood sampling. The blocking effect of P-gp was evaluated with tarquidar loading at a dose of 8 mg/kg. The total distribution volume (VT) of both tracers reflects P-gp function and was calculated by Logan graphical analysis using a metabolite-corrected plasma input function. Results: The baseline uptake of [11C]VER into the brain was low (standardized uptake value; SUV = 0.5-1) and stable till the end of PET measurements (90 min). After tarquidar infusion, the brain uptake of [11C]VER was significantly increased (SUV = 2-3) and peaked at 10 min after tracer injection, and then gradually decreased to SUV=1.5-2. The baseline uptake of [18F]MC225 was higher (SUV = 1-1.5) than [11C]VER and also stable till the end of PET measurements (90 min). After tarquidar infusion, the brain uptake of [18F]MC225 was significantly increased (SUV = 2-3) and peaked between 20 and 30 min after tracer injection, and then stable or slight decrease till the end of PET measurements. The whole brain baseline VT of [18F]MC225 (9.5) was 2.6-times higher than that of [11C]VER (3.6). Inhibition of P-gp resulted in a 3.2-times increase of whole brain VT (11.5) for [11C]VER. For [18F]MC225, the increase was 1.4-times in the whole brain (13.2). Conclusion: Our results confirm previous research with [18F]MC225 in rats and indicates that [18F]MC225 is a suitable tracer for measuring over-expression of P-gp at the human blood-brain barrier.
|Journal||European Journal of Nuclear Medicine and Molecular Imaging|
|Issue number||Suppl 2|
|Publication status||Published - 6-Oct-2017|
|Event||30th Annual Congress of the European Association of Nuclear Medicine (EANM'17) - Vienna, Austria|
Duration: 21-Oct-2017 → 25-Oct-2017
Conference number: 30th