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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

¹ Molecular Imaging Center, Mallinckrodt Institute of Radiology, St. Louis, Missouri
² Medical Science Division, Fox Chase Cancer Center, Philadelphia, Pennsylvania
³ Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, Missouri

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. Methods: Cell tracer transport experiments as well as mouse biodistribution and microPET imaging studies were performed to characterize a nonmetabolized gallium(III) complex, gallium(III)-(bis(3-ethoxy-2-hydroxy-benzylidene)-N,N'-bis(2,2-dimethyl-3-amino-propyl)ethylenediamine) (Ga-[3-ethoxy-ENBDMPI])⁺, as a candidate SPECT (⁶⁷Ga) and generator-produced PET (⁶⁸Ga) radiopharmaceutical recognized by MDR1 Pgp. Results: The ⁶⁷Ga-complex showed high membrane potential–dependent accumulation in drug-sensitive KB3-1 cells and modulator-reversible low accumulation in MDR KB8-5 cells. In KB8-5 cells, the median effective concentrations (EC₅₀) of MDR modulators LY335979, PSC 833, and cyclosporin A were 69 nmol/L, 1 µmol/L, and 3 µmol/L, respectively. Using a variety of cells stably expressing MDR1 Pgp, multidrug resistance–associated proteins (MRP1–MRP6), or the breast cancer resistance protein (BCRP/MXR), the ⁶⁷Ga-complex was shown to be readily transported by MDR1 Pgp and, to a much lesser extent, by MRP1, but not MRP2–MRP6 or BCRP/MXR. In a nude mouse xenograft tumor model, the ⁶⁷Ga-complex produced a readily detected 3-fold difference between Pgp-expressing tumors and drug-sensitive tumors in the opposite flank. In mdr1a/1b(–/–) gene–deleted 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. This could be readily observed with microPET using the ⁶⁸Ga-complex. Incidentally, wild-type mice showed heart-to-blood ratios of >100 by 1 h after injection and heart-to-liver ratios of 2.2 by 120 min. Conclusion: Molecular imaging of the functional transport activity of MDR1 Pgp with (^67/68Ga-[3-ethoxy-ENBDMPI])⁺ may enable noninvasive SPECT/PET monitoring of the blood–brain barrier, chemotherapeutic regimens, and MDR1 gene therapy protocols in vivo. These Pgp-directed properties of the radiopharmaceutical may also translate favorably to myocardial perfusion imaging.

Key Words: MDR1 P-glycoprotein • multidrug resistance • blood–brain barrier • perfusion imaging • ⁶⁷Ga/⁶⁸Ga radiopharmaceutical

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