New N(3)S donor ligand small peptide analogues of the N-mercaptoacetyl-glycylglycylglycine ligand in the clinically used Tc-99m renal imaging agent: evidence for unusual amide oxygen coordination by two new ligands.
Three new X-ray structurally characterized Re(V)O complexes, ReO(MEG(3)H(2)) (10), ReClO(MAEG(2)H(3)) (11), and [ReO(MECG(2)H(2))](2) (12), were prepared from protected forms of three new ligands, mercaptoethyl-glycylglycylglycine (MEG(3)H(5)), mercaptoacetamide-ethyl-glycylglycine (MAEG(2)H(5)), and mercaptoethyl-carbamoylmethyl-glycylglycine (MECG(2)H(5)). (Subscript on H indicates the number of dissociable protons.) Mercaptoacetyltriglycine (MAG(3)H(5)) is the ligand precursor for the clinically used Tc-99m renal imaging agent. The new potentially N(3)S donor ligands have a glycylglycine carboxyl end as in MAG(3)H(5), but a secondary amine (sp(3) N) replaces one amide (sp(2) N) of MAG(3)H(5). ReO(MEG(3)H(2)) (10) is a typical five-coordinate pseudo-square-pyramidal complex with the oxo ligand at the apex and the trianionic form of MEG(3)H(5) coordinated in the basal plane via N(3)S. In the other complexes, the quadridentate ligand has N(2)OS ligation, with the carbonyl oxygen of the glycyl amide group coordinated trans to the oxo ligand. This unusual ligation mode, which is facilitated by the preferred endo configuration of the ligated glycyl sp(3) N, leaves a vacant basal coordination site. In 11, the chloro ligand completes the equatorial plane, whereas, in 12, a glycine carboxylate oxygen of the ligand on the partner Re completes the equatorial plane. Both complexes thus possess an unexpected pseudo-octahedral geometry. For 10, 11, and 12, the (1)H NMR spectra, monitored from high to low pH, exhibited changes only when the pH was lowered below 6. This finding indicates that at physiological pH these complexes possess the desirable characteristic of existing as one monomeric species having only one ionization state, with the coordinated sp(3) N deprotonated. Below pH 6 and above pH approximately 4, changes in the (1)H NMR shifts indicate that this sp(3) N has become protonated. Thus, the N(3)S ligands in all three complexes exhibit normal coordination above pH approximately 4. However, X-ray data for 11 and 12 and some NMR evidence for 11 indicate that the ligands of the two complexes rearrange at low pH (<3). The striking differences between the solution- and solid-state structures reinforce the caveat that solution structural studies conducted at physiological pH are necessary in order to gain insight into the nature of radiopharmaceuticals.
Lipowska
Malgorzata
M
Department of Radiology, Emory University, Atlanta, Georgia 30322, USA.
Hansen
Lory
L
Xu
Xiaolong
X
Marzilli
Patricia A
PA
Taylor
Andrew
A
Marzilli
Luigi G
LG
D018360:Crystallography, X-Ray / Q000379:methods; D005998:Glycine; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D017672:Nitrogen Compounds / Q000737:chemistry; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry*; D012211:Rhenium / Q000737:chemistry; D013457:Sulfur Compounds / Q000737:chemistry; D017263:Technetium Tc 99m Mertiatide / Q000737:chemistry*
D008024:Ligands; D017672:Nitrogen Compounds; D009942:Organometallic Compounds; D010455:Peptides; D019275:Radiopharmaceuticals; D013457:Sulfur Compounds; D017263:Technetium Tc 99m Mertiatide; D012211:Rhenium; D005998:Glycine