Evaluating the Incorporation of Picolinamide Pendants into the Macropa Scaffold for Pb(II)- and Bi(III)-Based...

We report a detailed study on how the substitution of carboxylate groups of macropa for amides affects the coordination of Pb(II) and Bi(III). We describe a new synthesis of macropam, improving on previously reported yields. Pb(II) and Bi(III) complexes of macropa, macropapam, and macropam were prepared in situ and characterized. Crystal structures were obtained using XRD which were analyzed using eccentricity measurements and NBO analysis, showing that the lone pair is more active in Bi(III) complexes than in Pb(II) analogues and this activity decreases upon incorporation of amides. NMR and X-ray crystallography of [Bi(macropa)]⁺ evidenced a certain degree of fluxionality. This led to a detailed computational study in which the energies of the transition states for the switching of the X-CH₂-CH₂-X units of the macrocycle between λ and δ conformations were calculated. The relatively low energies of the transition states suggest that this process takes place in solution on the μs time scale. Radiolabeling with [²⁰³Pb]Pb(II) and [²¹³Bi]Bi(III) and stability assays of the [²⁰³Pb]Pb(II)-labeled complexes showed that the incorporation of amides worsens radiochemical performance. Overall, the incorporation of amides is detrimental for radiopharmaceutical applications, highlighting that as borderline acids, Pb(II) and Bi(III) at times prefer harder (negatively charged) donor atoms.