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

• Type of Material: Article
• Authors: Malgorzata Lipowska, Emory University; J Klenc, Emory University; Andrew Taylor Jr., Emory University; Luigi Marzilli, Emory University
• Language: English
• Date: 2019-02-24
• Publisher: Elsevier Science S.A.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier B.V.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ica.2018.11.012
• Title of Journal or Parent Work: Inorganica Chimica Acta
• Volume: 486
• Start Page: 529
• End Page: 537
• Grant/Funding Information: This research was supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant R37 DK038842.; We also acknowledge the use of the Rigaku SYNERGY diffractometer, supported by the National Science Foundation under grant CHE-1626172.
• Keywords: Amino acids; Tricarbonyl complexes; Geometric isomers; Chemistry, Inorganic & Nuclear; Science & Technology; Initial evaluation; Chemistry; X-ray structure; Structural characterization; RE; N-phosphonomethylglycine; Multidentate ligands; Rhenium(I); TC-99M; Phosphonate ligands; Renal tracer; Coordination chemistry; Technetium(I); Physical Sciences
• Research Categories: Health Sciences, Radiology; Chemistry, Radiation; Engineering, Biomedical

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.