Double-Armed 18- and 21-Membered Macrocycles as Potential Chelators for Lead and Bismuth Radiopharmaceuticals

Area of Science:

• Radiochemistry
• Nuclear Medicine
• Medicinal Chemistry

Background:

• Targeted alpha therapy (TAT) requires efficient chelating agents for radionuclides like lead-212 (212Pb) and bismuth-212/213 (212/213Bi).
• Existing chelators may lack rapid kinetics or sufficient kinetic inertness for clinical applications.

Purpose of the Study:

• To synthesize and characterize novel macrocyclic chelators (BADA and BADPA) for Pb2+ and Bi3+ complexation.
• To evaluate the radiolabeling kinetics, stability, and structural properties of these new chelating agents.
• To assess their potential for use in radiopharmaceuticals for targeted alpha therapy.

Main Methods:

• Synthesis of 18- and 21-membered macrocyclic ligands: diacetate (BADA) and dipicolinate (BADPA).
• Complexation studies using ESI-mass spectrometry, potentiometric titration, X-ray diffraction, and NMR spectroscopy.
• Radiolabeling with 210Pb and 207Bi, followed by in vitro stability assessments in serum and with competing metal ions.

Main Results:

• Successful synthesis of BADA and BADPA macrocyclic chelators.
• Established formation of mononuclear complexes and determined their stability constants.
• Demonstrated rapid complex formation (1-2 min at room temperature) and high kinetic inertness for Pb(BADPA-18) and Bi(BADPA-18) complexes in biological media.
• Complex stability is influenced by macrocycle size, ligand type (acetate vs. picolinate), ligand rigidity, and metal complex conformation.

Conclusions:

• The novel BADPA-18 ligand exhibits excellent properties for complexing Pb2+ and Bi3+.
• Rapid complexation and high kinetic inertness make BADPA-18 a promising candidate for developing radiopharmaceuticals for targeted alpha therapy.
• These findings contribute to the advancement of chelating agents for clinical radionuclide applications.