fac-99mTc/Re-tricarbonyl complexes with tridentate aminocarboxyphosphonate ligands: Suitability of the phosphonate group in chelate ligand design of new imaging agents

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/Retricarbonyl "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.

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“…Given the average circulating time of nanoDDS, radionuclides used for labeling NPs are usually those with long half-lives. Technetium-99 m is the most frequently utilized radionuclide because of its wide availability, low cost, and its long half-life (6 h), which permits an imaging window of up to 24 h. Isotopes of iodine and copper are also often used [ 83 ].…”

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“…These emitters can also induce the visualization of the cellular function and the monitoring of the molecular process in the cells. Technetium-99 m is frequently applied as radionuclide to radiolabel nanosytems, presumably because of its wide availability, low cost, favorable imaging properties and a half-life (6 h) that allows imaging for up to 24 h [58] . Indium-111 is the second most-used radionuclide, followed by radioisotopes of iodine [59] .…”

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