Abstract
Ligands that coordinate via dianionic phosphonate groups have not been widely utilized in radiopharmaceuticals. N-(phosphonomethyl)iminodiacetic acid (1, PMIDA) and N-(phosphonomethyl)glycine (2, PMG) were investigated as new chelators for the (99m)Tc/Re-tricarbonyl "core" (fac-M(CO)(3), M = (99m)Tc, Re) present in a major class of radiopharmaceuticals. fac-M(CO)(3)(PMIDA) and fac-M(CO)(3)(PMG) complexes were studied by HPLC and (1)H/(13)C/(31)P NMR methods for M = Re (Re-1 and Re-2) and by HPLC for M = (99m)Tc ( (99m) Tc-1 and (99m) Tc-2). Re-1 and (99m) Tc-1 complexes exhibit a similar pH-dependent equilibrium between geometric linkage isomers (M-1a and M-1b). However, only one isomer exists for M-2 under all conditions. Structural characterization by X-ray crystallography reveals the presence of a bond between a phosphonate oxygen and the Re(I) center in fac-Re(CO)(3)(PMG) (Re-2). Detailed comparisons of NMR data for Re-2 conclusively demonstrate that the phosphonate group is coordinated in Re-1b (isomer favored at high pH) but not in Re-1a, which has a dangling N-(phosphonomethyl) group. To our knowledge, Re-1b and Re-2 and their (99m)Tc analogs are the first well-documented examples of complexes with these metal-tricarbonyl cores having a dianionic phosphonate group directly coordinated in a fac-M(CO)(3)-O-P grouping. Pharmacokinetic studies using Sprague-Dawley rats reveal that (99m) Tc-2 is a robust tracer. Hence, phosphonate groups should be considered in designing (99m)Tc and (186/188)Re radiopharmaceuticals, including agents with bioactive moieties attached to dangling carboxylate or phosphonate groups.