Assessing p-glycoprotein (Pgp) activity in vivo utilizing 68Ga-Schiff base complexes.
OBJECTIVE
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.


METHODS
Six Schiff base compounds were synthesized and labeled with (68)Ge/(68)Ga generator-derived (68)Ga. 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 (68)Ga in yields of >92% 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, (68)Ga-ENBDMPI and (68)Ga-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 (68)Ga-labeled ligands appear to be valuable for imaging non-invasively the intratumoral Pgp activity. On a long term, patients with multidrug-resistant tumors pre-therapeutically may be identified prior to treatment.
Fellner
Marco
M
Institute of Nuclear Chemistry, University of Mainz, Mainz, Germany.
Dillenburg
Wolfgang
W
Buchholz
Hans-Georg
HG
Bausbacher
Nicole
N
Schreckenberger
Mathias
M
Renz
Franz
F
Rösch
Frank
F
Thews
Oliver
O
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D005708:Gallium / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D012545:Schiff Bases
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012545:Schiff Bases; D005708:Gallium
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