Macrocyclic and Hydroxamate Ligands for ²²⁵Ac Radiopharmaceuticals: Evaluating SSTR2-Targeting Potential

The development of effective radiopharmaceuticals requires careful consideration of the chelator properties and their impact on target receptor interactions. This study comprehensively investigated the molecular interactions between various ²²⁵Ac radiopharmaceuticals, differing in chelator structure, and somatostatin receptor 2 (SSTR2). The results indicated that 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene)phosphonic acid (DOTP) represents a promising alternative to the commonly used 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), likely due to its higher negative charge. Incorporation of a poly(ethylene glycol) linker (PEG4) between the chelator and the peptide moiety of the ligand significantly enhanced receptor activation. Density functional theory calculations identified hydroxamate ligands as potential alternatives to macrocyclic chelators, prompting the synthesis and characterization of a siderophore ligand, N1-[5-(Acetylhydroxyamino)pentyl]-N26-(5-aminopentyl)-N26,5,16-trihydroxy-4,12,15,23-tetraoxo-5,11,16,22-tetraazahexacosanediamide (DFO*), and its complexation with La³⁺ (a model for Ac³⁺) was confirmed by ¹H and ¹³⁹La NMR spectroscopy. While DFO* demonstrated high chelating ability and receptor recognition, its flexibility induced significant fluctuations atop the receptor. In contrast, the deoxy variant of the well-studied 3,4,3-LI(1,2-HOPO) ligand was identified as a structurally suitable chelating agent for ²²⁵Ac radiopharmaceuticals.