Influence of P-Glycoprotein Inhibition or Deficiency at the Blood–Brain Barrier on 18F-2-Fluoro-2-Deoxy-d-glucose (18F-FDG) Brain Kinetics

Abstract

The fluorinated d-glucose analog 18F-2-fluoro-2-deoxy-d-glucose (18F-FDG) is the most prevalent radiopharmaceutical for positron emission tomography (PET) imaging. P-Glycoprotein’s (P-gp, MDR1, and ABCB1) function in various cancer cell lines and tumors was shown to impact 18F-FDG incorporation, suggesting that P-gp function at the blood–brain barrier may also modulate 18F-FDG brain kinetics. We tested the influence of P-gp inhibition using the cyclosporine analog valspodar (PSC833; 5 μM) on the uptake of 18F-FDG in standardized human P-gp-overexpressing cells (MDCKII-MDR1). Consequences for 18F-FDG brain kinetics were then assessed using (i) 18F-FDG PET imaging and suitable kinetic modelling in baboons without or with P-gp inhibition by intravenous cyclosporine infusion (15 mg kg−1 h−1) and (ii) in situ brain perfusion in wild-type and P-gp/Bcrp (breast cancer resistance protein) knockout mice and controlled d-glucose exposure to the brain. In vitro, the time course of 18F-FDG uptake in MDR1 cells was influenced by the presence of valspodar in the absence of d-glucose but not in the presence of high d-glucose concentration. PET analysis revealed that P-gp inhibition had no significant impact on estimated brain kinetics parameters K1, k2, k3, VT, and CMRGlc. The lack of P-gp effect on in vivo18F-FDG brain distribution was confirmed in P-gp/Bcrp-deficient mice. P-gp inhibition indirectly modulates 18F-FDG uptake into P-gp-overexpressing cells, possibly through differences in the energetic cell level state. 18F-FDG is not a P-gp substrate at the BBB and 18F-FDG brain kinetics as well as estimated brain glucose metabolism are influenced by neither P-gp inhibition nor P-gp/Bcrp deficiencies in baboon and mice, respectively.