In Vivo Characterization of18F-AVT-011 as a Novel Radiotracer for PET Imaging of Multidrug Resistance

1230 Background: Multidrug resistance (MDR) impedes cancer treatment. Two efflux transporters from the ATP-binding cassette (ABC) family, ABCB1 and ABCG2, may contribute to MDR by restricting the entry of therapeutic drugs into tumors. Although higher expression of these transporters has been correlated with poorer clinical outcome, transporter expression does not necessarily correlate with function. In this study, we characterized the pharmacological properties of 18F-AVT-011, a PET radiotracer for imaging transporter function in tumors. Methods: AVT-011 was radiolabeled with 18F and evaluated with PET imaging in preclinical models. Specificity of 18F-AVT-011 for ABCB1 and ABCG2 was assessed by its uptake in the brains of wild-type, Abcb1a/b-/-, and Abcg2-/-mice, at baseline and after administration of the ABCB1 inhibitor tariquidar (n = 5/group). Metabolism and biodistribution of 18F-AVT-011 were also measured. To measure ABCB1 function in tumors, we performed PET experiments in mice bearing orthotopic breast tumors (n = 7-10/group) expressing basal to high levels of ABCB1 using both 18F-AVT-011 and 18F-FDG. A subset of animals (n = 3/group) was scanned before and after docetaxel treatment to calculate the effect size of MDR detectable by 18F-AVT-011. Results: At baseline, brain uptake was highest in Abcb1a/b-/-mice. After tariquidar administration, it increased 3-fold and 8-fold in wild-type and Abcg2-/-mice, respectively, but did not increase further in Abcb1a/b-/-mice. At 30 min after injection, the radiotracer was > 90% in its parent form and had highest uptake in organs of the hepatobiliary system. Uptake of 18F-AVT-011 was 32% lower in high-ABCB1 tumors than in basal-ABCB1 tumors, and it increased by 40% in high-ABCB1 tumors after tariquidar administration. Tumor uptake of 18F-FDG did not significantly differ among groups. The effect size of tumor uptake before and after chemotherapy was 1.16 in the basal group and 0.15 in the high-ABCB1 group. Conclusions: 18F-AVT-011 is a dual ABCB1/ABCG2 substrate radiotracer that can quantify transporter function at the blood-brain barrier and in tumors. Although the absolute levels of uptake are low, the radiotracer discriminates between tumors with basal and high levels of ABCB1, making it potentially suitable for clinical imaging of ABCB1-mediated MDR.