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A ⁶⁷Ga/⁶⁸Ga Radiopharmaceutical for SPECT and PET Imaging of MDR1 P-Glycoprotein Transport Activity In Vivo

Overexpression of multidrug resistance (MDR1) P-glycoprotein (Pgp) remains an important barrier to successful chemotherapy in cancer patients and impacts the pharmacokinetics of many important drugs, thus evoking a need to noninvasively interrogate Pgp transport activity in vivo. Cell tracer transport experiments as well as mouse biodistribution and microPET imaging studies were performed to characterize gallium(III)-(bis(3-ethoxy-2-hydroxybenzylidene)-N,N-bis(2,2-dimethyl-3-amino-propyl)ethylenediamine) [Ga-(3-ethoxy-ENBDMPI)]+, as a candidate SPECT (Ga-67) and generator-produced PET (Ga-68) radiopharmaceutical recognized by MDR1 Pgp. The 67Ga-complex showed high membrane potential-dependent accumulation in drug-sensitive KB 3-1 cells and modulator-reversible low accumulation in MDR KB 8-5 cells. In a nude mouse xenograft tumor model, the 67Ga-complex produced a 3-fold difference between Pgp-expressing tumors and drug-sensitive tumors. In mdr1a/1b(-/-) mice, the 67Ga-complex showed 17-fold greater brain uptake and retention compared with wild-type mice with no net difference in blood pharmacokinetics, consistent with transport in vivo by Pgp expressed at the capillary blood-brain barrier.
Figure 1
Chemical Structure of [Ga-(3-ethoxy-ENBDMPI)]+.
Figure 2
MicroPET image of 68Ga-complex in brains of FVB WT and mdr1a/1b(-/-) mice. After injection of mice with an intravenous bolus of radiopharmaceutical, images of abdomen, thorax, and head were obtained with microPET scanner. Representative coronal images of WT (left) and mdr1a/1b(-/-) (right) mice obtained 5 min after injection are shown. A body outline is included for orientation.
References:	Sharma V, Prior JL, Belinsky MG, Kruh GD, Piwnica-Worms D. Characterization of a 67Ga/68Ga radiopharmaceutical for SPECT and PET of MDR1 P-glycoprotein transport activity in vivo: validation in multidrug resistant tumors and at the blood-brain barrier. J Nucl Med 2005; 46(2): 354-64.	PubMed Link

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