We investigated nuclear medicine therapeutics targeting the L-type amino acid transporter 1 (LAT1). We previously reported that a nuclear medicine therapeutic drug using astatine 211 (²¹¹At), an alpha-emitting nuclide that can be produced in an accelerator and targets LAT1 as a molecular target, is effective. The seed compound was 3-[²¹¹At] Astato-α-methyl-L-tyrosine (²¹¹At-AAMT-OH-L). We used a unique labeling method. By changing the OH group of phenol to a methyl group, retention was successfully increased. It was also found that the amount of the L-isomer taken up by the D-isomer and L-isomer was clearly higher, and the L-isomer was superior as a therapeutic drug. Compounds in which the methyl group was replaced with an ethyl or propyl group were also examined, but their retention did not increase significantly. In fact, we observed increased non-specific accumulation and dynamics, suggesting that labeling may be off. In addition, ²¹¹At-AAMT-O-Me-L, which has a simple structure, was clearly superior in terms of uptake speed for several candidate compounds. As a result, we were able to develop a compound that can be easily labeled, has high specific radioactivity, is stable, and has a strong therapeutic effect.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality, with therapeutic resistance posing the primary barrier to durable outcomes. Beyond genetic and epigenetic alterations, amino acid transporter-driven metabolic reprogramming—mediated by LAT1 (SLC7A5), ASCT2 (SLC1A5), and xCT (SLC7A11)—supports tumor proliferation, redox homeostasis, and immune escape. Their preferential expression in NSCLC highlights their potential as therapeutic targets and predictive biomarkers. In parallel, α-particle therapy has gained attention for its capacity to eradicate resistant clones through densely clustered, irreparable DNA double-strand breaks. Astatine-211 (²¹¹At) combines a clinically relevant half-life, high linear energy transfer, and predictable decay scheme, positioning it as a unique candidate among α-emitters. Preclinical studies of ²¹¹At-labeled transporter ligands, particularly LAT1-targeted conjugates, demonstrate potent tumor suppression and synergy with targeted therapy, chemotherapy, radiotherapy, immunotherapy, and ferroptosis inducers. Advances in radiochemistry, delivery systems (antibodies, peptides, and nanocarriers), and PET tracers such as [¹⁸F]FAMT and [¹⁸F]FSPG collectively support a theranostic framework for patient stratification and adaptive dosing. By linking transporter biology with α-particle delivery, ²¹¹At-based theranostics offer a mechanistically orthogonal strategy to overcome resistance and heterogeneity in NSCLC. Successful translation will depend on precise dosimetry, scaffold stabilization, and biomarker-guided trial design, enabling progression toward first-in-human studies and future integration into multimodal NSCLC therapy.

Novel nuclear medicine therapeutics are being developed by labeling medium-molecular-weight compounds with short-lived alpha-emitting radionuclides. Fibroblast activation protein α (FAPα) is recognized as a highly useful molecular target, and its inhibitor, FAPI, is a compound capable of theranostics, both therapeutic and diagnostic, for cancer treatment. In this study, we compared the functions of two compounds that target FAPα: ²¹¹At-FAPI1 and ²¹¹At-FAPI2. First, in vitro screening procedures are generally accepted because of the low endogenous expression of FAPα. We suggest the usefulness of this 3D culture system for in vitro screening. Second, when FAPIs are used therapeutically, the expected therapeutic effects are often not achieved. Therefore, we compared the accumulation and excretion in tumor tissues and the anti-tumor effects based on the length of the linker in the compounds. The compounds were rapidly labeled using the Shirakami reaction. Doubling the linker length increased tumor retention. Additionally, the excretion pathway was altered, suggesting a potential reduction in toxicity. Although no significant differences were observed in the anti-tumor effects of ²¹¹At-FAPI1 and ²¹¹At-FAPI2, it was confirmed that the linker length affects the biological half-life.

This study investigated the distribution and dispersion of Sc-47 (⁴⁷Sc), a β-emitting radionuclide that can be produced in large quantities using accelerators. As the stability of labeled compounds inside the body is essential for nuclear medicine therapy, we examined the biodistribution of free ⁴⁷Sc to distinguish it from the distribution of compounds labeled with ⁴⁷Sc. [⁴⁷Sc]ScCl₃ was administered to normal mice. Body distribution, excretion routes, and contamination of laboratory equipment were also measured. ⁴⁷Sc remained in the blood for long periods and accumulated mainly in the liver and kidneys because of its binding to plasma proteins. Therefore, ⁴⁷Sc released from the labeled compounds could potentially cause non-specific liver and kidney damage. Most of the ⁴⁷Sc was eliminated through feces, whereas some was excreted through the urinary system. ⁴⁷Sc was found in both the liquid and solid components of the blood. Although animal cages were contaminated with excreta, they could be effectively cleaned by wiping with paper. We also used ⁴⁷Sc produced by us to label PSMA-617 and verified its performance as a nuclear medicine therapeutic agent. Although [⁴⁷Sc]Sc-PSMA-617 did not exhibit a high accumulation rate in tumors, it demonstrated antitumor activity. This might suggest the usefulness of ⁴⁷Sc.