Different Efflux Transporter Affinity and Metabolism of .sup.99mTc-2-Methoxyisobutylisonitrile and .sup.99mTc-Tetrofosmin for Multidrug Resistance Monitoring in Cancer

Background Little is known about the affinity and stability of .sup.99mTc-labeled 2-methoxyisobutylisonitrile (.sup.99mTc-MIBI) and tetrofosmin (.sup.99mTc-TF) for imaging of multiple drug resistance transporters in cancer. We examined the affinity of .sup.99mTc-labeled compounds for these transporters and their stability. Methods .sup.99mTc-MIBI and .sup.99mTc-TF were incubated in vesicles expressing P-glycoprotein (MDR1), multidrug resistance-associated protein (MRP)1-4, or breast cancer resistance protein with and without verapamil (MDR1 inhibitor) or MK-571 (MRP inhibitor). Time activity curves of .sup.99mTc-labeled compounds were established using SK-N-SH neuroblastoma, SK-MEL-28 melanoma, and PC-3 prostate adenocarcinoma cell lines, and transporter expression of multiple drug resistance was measured in these cells. The stability was evaluated. Results In vesicles, .sup.99mTc-labeled compounds had affinity for MDR1 and MRP1. .sup.99mTc-TF had additional affinity for MRP2 and MRP3. In SK-N-SH cells expressing MDR1 and MRP1, MK-571 produced the highest uptake of both .sup.99mTc-labeled compounds. .sup.99mTc-MIBI uptake with inhibitors was higher than .sup.99mTc-TF uptake with inhibitors. .sup.99mTc-TF was taken up more in SK-MEL-28 cells expressing MRP1 and MRP2 than PC-3 cells expressing MRP1 and MRP3. .sup.99mTc-MIBI was metabolized, whereas .sup.99mTc-TF had high stability. Conclusion .sup.99mTc-MIBI is exported via MDR1 and MRP1 (MRP1 > MDR1) at greater levels and more quickly compared to .sup.99mTc-TF, which is exported via MDR1 and MRP1-3 (MRP1 > MDR1; MRP1, 2 > MRP3). Because .sup.99mTc-MIBI is metabolized, clinical imaging for monitoring MDR and shorter examination times may be possible with an earlier scanning time on late phase imaging. .sup.99mTc-TF has high stability and accurately reflects the function of MDR1 and MRP1-3.