Imaging changes of P-glycoprotein activity in vivo with 68Ga-Schiff base derivatives

Objectives P-glycoprotein (pGP), an active drug transporter, pumps a wide number of xenobiotics (e.g. chemotherapeutics) out of the cell. Since many tumours overexpress pGP, the cytotoxicity of these drugs is reduced leading to multidrug resistance. In vitro it has been shown that the activity of pGP can be increased by extracellular acidosis. Here MAP kinases (p38, ERK1/2) seem to play an important role. With the Schiff base complex 68Ga-MFL6.MZ it became possible to visualize the functional activity of the pGP in vivo by means of µ-PET.

Methods The ligand MFL6.MZ was labelled with the positron emitter 68Ga in a fast and easy process (95% yield after 10 min), ready for injection. Tumours were induced by subcutaneous injection of R3327-AT1 cells into the hind foot dorsum of male Copenhagen rats. Acidification achieved by injection of small amounts of lactic acid directly into the tumour. MAP kinases were inhibited by injection of SB203580 (p38) and U0126 (ERK1/2). Uptake of 68Ga-MFL6.MZ was determined both ex vivo and in vivo using µPET imaging.

Results Acidifying the tumour led to local reduction of the tracer accumulation indicating a higher pGP transport activity. The tracer concentration of acidified tumours was only 80% of controls. In contrast, MAP kinase inhibitors reduced pGP transport rate which resulted in a higher tracer accumulation. Inhibition of p38 led to almost a doubling of the tracer activity compared to control tumour, whereas with the ERK1/2 inhibitor the concentration increased by 30%.

Conclusions The new PET tracer 68Ga-MFL6.MZ reveals that an acidic extracellular environment activates the pGP markedly. The p38-MAPK pathway plays an important role for the pGP regulation in vivo, whereas ERK1/2 is of minor importance. From these results new strategies for overcoming multidrug resistance (e.g., inhibition of p38) may be developed