TOWARD HIGHLY STABLE [212/203Pb]Pb²⁺ COMPLEXES: RIGIDIFIED HEXADENTATE LIGAND DESIGN

Aim/Introduction: The theranostic approach exploits the same drug delivery system with either diagnostic or therapeutic radionuclide, allowing an accurate prediction of the therapeutic biodistribution. Lead-203 (203Pb, t1/2 51.9 h, γ, 80.94 %) and lead-212 (212Pb, t1/2 = 10.6 h, β-, 100% followed by a decay chain including α-emission) are one example of a true theranostic pair. This study reports two hexadentate acyclic chelators based on a rigid trans-diaminocyclohexane (DACH) scaffold [Figure 1] to improve both thermodynamic stability and kinetic intertness of the Pb2+ complexes. Materials and Methods: Thermodynamic and kinetic studies were performed combining potentiometry, UV-Vis and 1H NMR spectroscopy. 203Pb was produced via the 203Tl (p,n)203Pb reaction at TRIUMF’s TR13 cyclotron. Concentration-, time-, temperature-dependent radiolabelling with 203Pb were conducted at pH 6 (0.1 M NH4OAc). The radiochemical yields (RCYs) were determined by radio-TLC. The in vitro stability of the preformed 203Pb complex was assessed in human serum over 48 h by radio-TLC. Results: H2bpcd and NH2bpcd combine pyridine and carboxylate/carboxamide donor groups creating an N4O2 coordination environment. NMR complexation studies with natPb2+ show that both ligands have good affinity for Pb2+, revealing rapid complex formation and high stability in acidic conditions (pH ~1). However, the two complexes differ in the isomerization profiles: H2bpcd forms one dominant species in solution, while NH2bpcd yields two isomers. These results are further confirmed by DFT calculations. Thermodynamic studies reveal a significantly higher thermodynamic stability of H2bpcd compared to NH2bpcd, with the former establishing a new benchmark among acyclic ligands for Pb2+ (pPb2+ 15.9 vs 9.7 for DTPAm and 14.8 for H2ampa). [203Pb]Pb2+ radiolabeling experiments show that only H2bpcd can incorporate the radiometal (RCY% > 95%, [H2bpcd] = 10-5 M, pH 6, 15 min, RT/80°C) while NH2bpcd shows poor radiolabeling efficiency. Conclusions: This study pinpoints H2bpcd as a promising scaffold capable of forming highly stable natPb2+ complexes and efficiently binding [203Pb]Pb2+. These findings provide strong support for further (pre)clinical translation of 212/203Pb-labelled radiotracers.