Bispidine Chelators for Radiopharmaceutical Applications with Lanthanide, Actinide, and Main Group Metal Ions

Area of Science:

• Radiopharmaceutical Chemistry
• Coordination Chemistry
• Nuclear Medicine

Background:

• Bispidine scaffolds form highly stable metal complexes for radiopharmaceutical applications.
• Nonadentate bispidine L^ is an effective chelator for diagnostic and therapeutic radionuclides like In-111, Lu-3+, and Ac-225.
• Previous studies demonstrated the theranostic potential of L^ with SSTR2-targeted agents.

Purpose of the Study:

• To synthesize and evaluate a new bispidine ligand derivative, L^, with a terpyridine moiety for improved metal ion coordination.
• To investigate the coordination chemistry of L^ with various metal ions, including Bi3+, La3+, and Pb2+.
• To assess the stability and radiolabeling efficiency of L^ complexes for diagnostic and therapeutic applications.

Main Methods:

• Synthesis and characterization of the novel bispidine ligand L^.
• Complexation studies with various metal ions (Bi3+, La3+, Lu3+, Ac3+, In3+, Pb2+).
• Radiolabeling and radiostability studies under physiological conditions.
• Preliminary density functional theory (DFT) analysis of complexation pathways.

Main Results:

• Ligand L^ demonstrated efficient complexation with Bi3+ and Pb2+, but less so with Lu3+, La3+, and Ac3+ compared to L^.
• Ac-225 complexation with L^ yielded 92% radiochemical yield under optimized conditions (80 °C, 60 min).
• L^ forms stable and inert complexes with a range of medically relevant metal ions (La3+, Ac3+, Lu3+, Bi3+, In3+, Pb2+) under physiological conditions.
• Daughter nuclides of Ac-225 (Bi-213, Pb-209) also form stable complexes with L^, crucial for targeted alpha therapy.

Conclusions:

• The bispidine scaffold remains a versatile platform for developing radiometal chelators.
• Ligand L^ shows potential for targeted alpha therapy, particularly with Ac-225 and its decay products.
• Further optimization of bispidine chelators is guided by understanding complexation pathways and DFT analysis.