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

Inorg Chem. 2024 Nov 11;63(45):21652-21669. doi: 10.1021/acs.inorgchem.4c03116. Epub 2024 Oct 30.

Abstract

With increasing clinical applications and interest in targeted alpha therapy, there is growing interest in developing alternative chelating agents for [212Pb]Pb2+ and [212/213Bi]Bi3+ that exhibit rapid radiolabeling kinetics and kinetic inertness. Herein we report the synthesis and detailed investigation of diacetate and dipicolinate 18- and 21-membered macrocyclic chelators BADA-18, BADA-21, BADPA-18, and BADPA-21 for the complexation of Pb2+ and Bi3+ ions with potential use in the preparation of radiopharmaceuticals. The formation of mononuclear complexes was established by using ESI-mass spectrometry, and their stability constants were determined by potentiometric titration. A thorough study of the structure of the metal complexes was carried out by using X-ray diffraction and NMR spectroscopy. It was shown how the stability of the complex is influenced by an increase in the size of the macrocycle, the replacement of acetate arms with picolinate ones, the rigidity of the ligand, as well as the type of conformation (syn- or anti-) of the metal complex. The new ligands were radiolabeled with [210Pb]Pb2+ and [207Bi]Bi3+, and the in vitro stability of the resulting complexes in a competitive environment of serum and biologically significant metal ions was assessed. Rapid complex formation in 1-2 min at room temperature, as well as the high kinetic inertness of the complexes Pb(BADPA-18) and Bi(BADPA-18) in biological media, demonstrate its potential for use in targeted radionuclide therapy.

MeSH terms

  • Bismuth* / chemistry
  • Chelating Agents* / chemical synthesis
  • Chelating Agents* / chemistry
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology
  • Lead / chemistry
  • Lead Radioisotopes / chemistry
  • Macrocyclic Compounds* / chemical synthesis
  • Macrocyclic Compounds* / chemistry
  • Molecular Structure
  • Radiopharmaceuticals* / chemical synthesis
  • Radiopharmaceuticals* / chemistry
  • Radiopharmaceuticals* / pharmacology

Substances

  • Bismuth
  • Chelating Agents
  • Radiopharmaceuticals
  • Macrocyclic Compounds
  • Coordination Complexes
  • Lead
  • Lead Radioisotopes