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Simple Summary  To enhance the therapeutic effect of 2- 211 At-astato-α-methyl-L-phenylalanine (2- 211 At-AAMP), a radiopharmaceutical for targeted alpha therapy, we evaluated the effect of probenecid loading on its biodistribution and therapeutic effect in mice. Probenecid preloading significantly delayed the clearance of 2- 211 At-AAMP from the blood, increasing its accumulation in tumors. Consequently, the therapeutic effect of 2- 211 At-AAMP markedly improved. These results indicate that 2- 211 At-AAMP with probenecid loading is useful for the treatment of various types of cancers.    Abstract  L-type amino acid transporter 1 (LAT1) might be a useful target for tumor therapy since it is highly expressed in various types of cancers. We previously developed an astatine-211 ( 211 At)-labeled amino acid derivative, 2- 211 At-astato-α-methyl-L-phenylalanine (2- 211 At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2- 211 At-AAMP was insufficient, probably due to its low tumor retention. The preloading of probenecid, an organic anion transporter inhibitor, can delay the clearance of some amino acid tracers from the blood and consequently increase their accumulation in tumors. In this study, we evaluated the effect of probenecid preloading on the biodistribution and therapeutic effect of 2- 211 At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2- 211 At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2- 211 At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2- 211 At-AAMP with probenecid, and the tumor volume was significantly lower in the treatment group than in the untreated control group from day 2 to day 30 (end of the follow-up period) after treatment. These results indicate that probenecid loading could improve the therapeutic effect of 2- 211 At-AAMP by increasing its accumulation in tumors.

Enhancing the Therapeutic Effect of 2-211At-astato-α-methyl-L-phenylalanine with Probenecid Loading