Influence of Functionalized Pyridine Ligands on the Radio/Chemical Behavior of [MI(CO)3]+ (M = Re and 99mTc) 2+1 Complexes

While a number of chelate strategies have been developed for the organometallic precursor fac-[M-I(OH2)(3)(CO)(3)](+) (M = Re, Tc-99m), a unique challenge has been to improve the overall function and performance of these complexes for in vivo and in vitro applications. Since its discovery, fac-[MI(OH2)(3)(CO)(3)](+) has served as an essential scaffold for the development of new targeted Tc-99m based radiopharmaceuticals due to its labile aquo ligands. However, the lipophilic nature of the fac-[MI(CO)(3)](+) core can influence the in vivo pharmacokinetics and biodistribution of the complexes. In an effort to understand and improve this behavior, monosubstituted pyridine ligands were used to assess the impact of donor nitrogen basicity on binding strength and stability of fac-[MI(CO)(3)](+) in a 2 + 1 labeling strategy. A series of Re and Tc-99m complexes were synthesized with picolinic acid as a bidentate ligand and 4-substituted pyridine ligands. These complexes were designed to probe the effect of pK(a) from the monodentate pyridine ligand both at the macro scale and radiochemical concentrations. Comparison of X-ray structural data and radiochemical solution experiments clearly indicate an increase in overall yield and stability as pyridine basicity increased.