Assessing p-Glycoprotein (Pgp) Activity In Vivo Utilizing 68Ga–Schiff Base Complexes

Purpose: The p-glycoprotein (Pgp) is the most prominent member of active drug transporters leading to a multidrug-resistant phenotype. For identification of tumors functionally overexpressing Pgp in vivo, non-invasive imaging techniques are needed. Procedures: Six Schiff base compounds were synthesized and labeled with ⁶⁸Ge/ ⁶⁸Ga generator-derived ⁶⁸Ga. The compounds were studied in vitro in Pgp-positive tumor cells. The property of being a Pgp substrate was tested by comparison of the tracers uptake in R-3327 Dunning prostate carcinoma AT1 cells in presence and absence of the Pgp-inhibitor verapamil. In vivo investigations were performed with tumor-bearing rats imaged with micro-positron emission tomography. Results: All ligands were labeled with ⁶⁸Ga in yields of 992% beside one (̃55%). The tracers showed different accumulation within the cells in vitro (4-60%). In blocking experiments, the ratio (blocked to unblocked) varied from 1.8 to 1.0. For in vivo experiments, ⁶⁸Ga-ENBDMPI and ⁶⁸Ga-MFL6.MZ were selected. The tumors showed specific uptake of the tracer. Direct intratumoral injection of verapamil increased the tracer concentration by ̃25% reflecting the functional Pgp activity. Conclusions: Two ⁶⁸Ga-labeled ligands appear to be valuable for imaging non-invasively the intratumoral Pgp activity. On a long term, patients with multidrug-resistant tumors pretherapeutically may be identified prior to treatment.