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

• Authors: Malgorzata Lipowska, Emory University; J Klenc, Emory University; Andrew Taylor Jr., Emory University; Luigi Marzilli, Emory University
• Journal Title: Inorganica Chimica Acta
• Volume: Volume 486
• Publisher: Elsevier Science S.A. | 2019-02-24, Pages 529-537
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.ica.2018.11.012
• Subjects: Health Sciences, Radiology; Chemistry, Radiation; Engineering, Biomedical
• Keywords: Science & Technology; Physical Sciences; Chemistry, Inorganic & Nuclear; Chemistry; Rhenium(I); Technetium(I); Tricarbonyl complexes; Phosphonate ligands; X-ray structure; Geometric isomers; Structural characterization; N-phosphonomethylglycine; Coordination chemistry; Tricarbonyl complexes; Multidentate ligands; Initial evaluation; Renal tracer; Amino acids; TC-99M; RE

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 99mTc/Re-tricarbonyl “core” (fac-M(CO)3, M = 99mTc, 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 1H/13C/31P NMR methods for M = Re (Re-1 and Re-2) and by HPLC for M = 99mTc (99mTc-1 and 99mTc-2). Re-1 and 99mTc-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 99mTc 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 99mTc-2 is a robust tracer. Hence, phosphonate groups should be considered in designing 99mTc and 186/188Re radiopharmaceuticals, including agents with bioactive moieties attached to dangling carboxylate or phosphonate groups.