Rearmed Bifunctional Chelating Ligand for ²²⁵Ac/¹⁵⁵Tb Precision-Guided Theranostic Radiopharmaceuticals─H₄noneunpaX.

Area of Science:

• Radiochemistry and Nuclear Medicine
• Advanced chelating ligand design
• Theranostic applications in oncology

Background:

• Targeted alpha therapy (TAT) requires bifunctional chelators for alpha-emitters and diagnostic isotopes.
• Existing chelators face challenges in complexing both radionuclide types for theranostics.
• Clinical translation of TAT with integrated diagnostics is hindered by ligand limitations.

Purpose of the Study:

• To develop a novel chelating ligand, H4noneupaX, for simultaneous complexation of alpha-emitters and diagnostic radionuclides.
• To evaluate the stability and kinetic inertness of H4noneupaX complexes with relevant metal ions.
• To assess the in vivo performance of H4noneupaX for theranostic applications.

Main Methods:

• Synthesis and characterization of the H4noneupaX ligand.
• Thermodynamic and kinetic stability studies of metal complexes (Ln3+, An3+).
• Radiolabeling studies with 111In, 155Tb, 177Lu, and 225Ac.
• In vivo evaluation using 155Tb-labeled conjugates in tumor-bearing mouse models (SPECT/CT, biodistribution).

Main Results:

• H4noneupaX forms thermodynamically stable and kinetically inert complexes with target metal ions.
• High molar activities achieved for 111In, 155Tb, 177Lu, and 225Ac under mild conditions.
• In vivo studies demonstrated excellent image contrast, tumor uptake, and stability of 155Tb-H4noneupaX conjugates.

Conclusions:

• H4noneupaX is a superior bifunctional chelating ligand for theranostic applications.
• The ligand enables efficient radiolabeling and exhibits promising in vivo performance.
• H4noneupaX shows significant potential for clinical translation of 225Ac/155Tb and 177Lu/155Tb theranostics.