Getting A Lead On Pb2+-Amide Chelators For Pb-203/212 Radiopharmaceuticals

Amide-based chelators DTPAm, EGTAm and ampam were synthesized to investigate which chelator most ideally coordinates [Pb-nat/203]Pb2+ ions for potential radiopharmaceutical applications. H-1 NMR spectroscopy was used to study each metal-ligand complex in the solution state. The H-1 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 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 Pb2+ ions was tested by [Pb-203]Pb2+ radiolabeling studies to evaluate their prospects as chelators for [Pb-203/212]Pb2+-based radiopharmaceuticals. DTPAm radiolabeled [Pb-203]Pb2+ ions achieving molar activities as high as 3.5 MBq mu mol(-1) within 15 minutes, at 25 degrees C, whereas EGTAm and ampam produced lower molar activities of 0.25 MBq mu mol(-1) within 30 minutes, at 37 degrees C. EGTAm and ampam were therefore deemed unsuitable for [Pb-203/212]Pb2+-based radiopharmaceutical applications, while DTPAm warrants further studies.