PET Imaging of the Impact of Extracellular pH and MAP Kinases on the p-Glycoprotein (Pgp) Activity

Abstract

The functional activity of p-glycoprotein (Pgp) can be increased in vitro by an extracellular acidosis via activation of MAP kinases (p38, ERK1/2). In order to study these effects in vivo a new ⁶⁸Ga-labeled PET tracer was developed which serves as a substrate of the Pgp and therefore indirectly mirrors the Pgp activity. For in vivo studies, experimental tumors were imaged under acidic conditions (inspiratory hypoxia, injection of lactic acid) and during inhibition of MAP kinases in a μ-PET system. In vitro, [⁶⁸Ga]MFL6.MZ showed an accumulation within the cells of about 20% which was increased to 30% by Pgp inhibition. In solid tumors a marked tracer uptake was observed showing spatial heterogeneity. When the tumors were acidified, the PET tracer accumulation was reduced by 20–30%. Changing the inspiratory O₂-fraction to 8% led dynamically to a decrease in pH and in parallel to a reduced tracer concentration. Inhibition of the p38 pathway reduced the Pgp transport rate. The new ⁶⁸Ga-labeled tracer is suitable for PET imaging of the tissue Pgp activity. In vivo imaging reveals that an acidosis activates the Pgp markedly, a mechanism in which the p38-MAPK pathway seems to play an important role.

This study forms part of the doctoral thesis of Wolfgang Dillenburg.