Getting a lead on Pb²⁺-amide chelators for ^203/212Pb radiopharmaceuticals

Amide-based chelators DTPAm, EGTAm and ampam were synthesized to investigate which chelator most ideally coordinates [^nat/203Pb]Pb²⁺ ions for potential radiopharmaceutical applications. ¹H NMR spectroscopy was used to study each metal-ligand complex in the solution state. The ¹H NMR spectrum of [Pb(DTPAm)]²⁺ revealed minimal isomerization and fluxional behaviour compared to [Pb(EGTAm)]²⁺ and [Pb(ampam)]²⁺, both of which showed fewer spectral changes indicative of less static behaviour. The solid-state coordination properties of each complex were also examined from single crystal structures that were studied by X-ray diffraction (XRD). In the solid-state, octadentate DTPAm coordinated Pb²⁺ to form an eight-coordinate hemidirected complex; octadentate EGTAm coordinated Pb²⁺ forming a ten-coordinate holodirected complex with a bidentate NO₃^- ion also coordinated to the metal centre; decadentate ampam completely encapsulated the Pb²⁺ ion to form a ten-coordinate holodirected complex with a C₂ axis of symmetry. Potentiometric titrations were carried out to assess the thermodynamic stability of each metal-ligand complex. The pM values obtained for [Pb(DTPAm)]²⁺, [Pb(EGTAm)]²⁺ and [Pb(ampam)]²⁺ were 9.7, 7.2 and 10.2, respectively. The affinity of each chelator for Pb²⁺ ions was tested by [²⁰³Pb]Pb²⁺ radiolabeling studies to evaluate their prospects as chelators for [^203/212Pb]Pb²⁺-based radiopharmaceuticals. DTPAm radiolabeled [²⁰³Pb]Pb²⁺ ions achieving molar activities as high as 3.5 MBq μmol^-1 within 15 minutes, at 25 °C, whereas EGTAm and ampam produced lower molar activities of 0.25 MBq μmol^-1 within 30 minutes, at 37 °C. EGTAm and ampam were therefore deemed unsuitable for [^203/212Pb]Pb²⁺-based radiopharmaceutical applications, while DTPAm warrants further studies.