Preclinical evaluation of new α-radionuclide therapy targeting LAT1: 2-[211At]astato-α-methyl-L-phenylalanine in tumor-bearing model

Targeted α-radionuclide therapy has growing attention as a promising therapy for refractory cancers. However, the application is limited to certain types of cancer. Since L-type amino acid transporter 1 (LAT1) is highly expressed in various human cancers, we prepared LAT1-selective α-emitting amino acid analog, 2-[211At]astato-α-methyl-L-phenylalanine (2-[211At]AAMP), and evaluated its potential as a therapeutic agent. Methods: 2-[211At]AAMP was prepared from the stannyl precursor. Stability of 2-[211At]AAMP was evaluated by both in vitro and in vivo. In vitro studies using LAT1 expressing human ovarian cancer cell line, SKOV3, were performed for evaluating cellular uptake and cytotoxicity of 2-[211At]AAMP. Biodistribution and therapeutic studies in SKOV3 bearing mice were performed after intravenous injection of 2-[211At]AAMP. Results: 2-[211At]AAMP was stable in murine plasma in vitro and excreted into urine as intact. Cellular uptake of 2-[211At]AAMP was inhibited by treatment with LAT1-selective inhibitor. After 24 hours of incubation, 2-[211At]AAMP suppressed clonogenic growth at 10 kBq/ml, and induced cell death and DNA double-strand break at 25 kBq/ml. When injected to mice, 2-[211At]AAMP exhibited the peak accumulation in the tumor at 30 min postinjection, and the radioactivity levels in the tumor retained up to 60 min. The majority of the radioactivity was rapidly eliminated from the body into the urine as an intact form immediately after injection. 2-[211At]AAMP significantly improved the survival of mice (P