Getting a lead on Pb 2+ -amide chelators for 203/212 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.