Development of Novel 211At-Labeled Agent for Neurotensin Receptor 1-Targeted α-Particle Therapy

Abstract Neurotensin receptor 1 (NTSR1) is overexpressed in various types of cancer and known as a promising target for cancer therapy. Targeted alpha therapy (TAT) using α-emitting radionuclides with high linear energy transfer is expected to show potent therapeutic efficacy. In this study, we aimed to develop an 211At-labeled NTSR1-TAT agent. To achieve this, [125I]IB-NTS, [125I]IB-DOTA-NTS, and [125I]IB-In-DOTA-NTS were newly designed, synthesized, and evaluated using 125I as a surrogate radionuclide. These 125I-labeled compounds showed high stability in murine plasma and NTSR1-binding affinity. In the biodistribution study, [125I]IB-In-DOTA-NTS demonstrated the most favorable tumor uptake among the three compounds and in vivo NTSR1-specificity. Therefore, [211At]AB-In-DOTA-NTS was synthesized and its utility as an NTSR1-TAT agent was evaluated. [211At]AB-In-DOTA-NTS exhibited dose-dependent antitumor effects without sustained or dose-dependent body weight loss in HT-29 tumor-bearing mice. This study demonstrated that [211At]AB-In-DOTA-NTS is a promising candidate for TAT and represents the first report of an 211At-labeled NTSR1-TAT agent.