Getting a lead on Pb-amide chelators for Pb radiopharmaceuticals

Amide-based chelators DTPAm, EGTAm and ampam were synthesized to investigate which chelator most ideally coordinates [ nat/203 Pb]Pb 2+ ions for potential radiopharmaceutical applications. 1 H NMR spectroscopy was used to study each metal-ligand complex in the solution state. The 1 H 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 Pb 2+ to form an eight-coordinate hemidirected complex; octadentate EGTAm coordinated Pb 2+ forming a ten-coordinate holodirected complex with a bidentate NO 3 − ion also coordinated to the metal centre; decadentate ampam completely encapsulated the Pb 2+ ion to form a ten-coordinate holodirected complex with a C 2 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 Pb 2+ ions was tested by [ 203 Pb]Pb 2+ radiolabeling studies to evaluate their prospects as chelators for [ 203/212 Pb]Pb 2+ -based radiopharmaceuticals. DTPAm radiolabeled [ 203 Pb]Pb 2+ 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 [ 203/212 Pb]Pb 2+ -based radiopharmaceutical applications, while DTPAm warrants further studies. Three chelators were developed for potential use in 203/212 Pb-based radiopharmaceuticals. Studies probing the coordination chemistry of the metal complexes and radiolabeling capabilities revealed a compound for future study.