Molecular Dynamics Simulation-Guided 124I/211At-Labeled Aromatic Amide Derivatives as a Potential Theranostic Pair for Melanoma

Abstract Targeted alpha therapy (TAT) based on 211At represents a highly promising therapeutic strategy for various cancers, yet the rational design of molecular structures remains challenging in practical translation. In this work, we proposed a molecular dynamics (MD) simulation-guided strategy for constructing 124I/211At-labeled aromatic amide derivatives as a potential theranostic pair for melanoma. The interaction process between melanin and a series of aromatic amide derivatives was first investigated via MD simulation, emphasizing that dimethylamino derivatives possessed superior binding ability. Furthermore, radioiodinated dimethylamino derivative [124I]Dm-5-IPLA was proven to have the best tumor-targeting capability and favorable pharmacokinetics via systematic experimental investigations including in vitro cell testing, in vivo PET imaging, and ex vivo biodistribution investigations. Its therapeutic analogue, [211At]Dm-5-APLA, accordingly exhibited effective tumor growth inhibition and satisfactory safety in the TAT of B16F10 tumor-bearing mice, indicating the potential of 124I/211At-labeled aromatic amide derivatives for melanoma theranostics.