title: 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 (68)Ga-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, [(68)Ga]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 O(2)-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 (68)Ga-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.
authors.affiliation: Julius-Bernstein Institute of Physiology, University of Halle-Wittenberg, Magdeburger Str. 6, 06112, Halle (Saale), Germany. oliver.thews@medizin.uni-halle.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Thews
authors.affiliation: Institute of Physiology and Pathophysiology, University Medicine Mainz, Mainz, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dillenburg
authors.affiliation: Institute of Nuclear Chemistry, University of Mainz, Mainz, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Rösch
authors.affiliation: Institute of Nuclear Chemistry, University of Mainz, Mainz, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Fellner
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000138:Acidosis / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005710:Gallium Radioisotopes; D006863:Hydrogen-Ion Concentration; D008297:Male; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005710:Gallium Radioisotopes; D048051:p38 Mitogen-Activated Protein Kinases