Lanthanide chelates of (bis)-hydroxymethyl-substituted DTTA with potential application as contrast agents in magnetic resonance imaging.
A novel bis-hydroxymethyl-substituted DTTA chelator N'-Bz-C(4,4')-(CH(2)OH)(2)-DTTA () and its DTPA analogue C(4,4')-(CH(2)OH)(2)-DTPA () were synthesized and characterized. A variable-temperature (1)H NMR spectroscopy study of the solution dynamics of their diamagnetic (La) and paramagnetic (Sm, Eu) Ln(3+) complexes showed them to be rigid when compared with analogous Ln(3+)-DTTA and Ln(3+)-DTPA complexes, as a result of their C(4,4')-(CH(2)OH)(2) ligand backbone substitution. The parameters that govern the water (1)H relaxivity of the [Gd()(H(2)O)(2)](-) and [Gd()(H(2)O)](2-) complexes were obtained by (17)O and (1)H NMR relaxometry. While the relaxometric behaviour of the [Gd()(H(2)O)](2-) complex is very similar to the parent [Gd(DTPA)(H(2)O)](2-) system, the [Gd()(H(2)O)(2)](-) complex displays higher relaxivity, due to the presence of two inner sphere water molecules and an accelerated, near optimal water exchange rate. The [Gd()(H(2)O)(2)](-) complex interacts weakly with human serum albumin (HSA), and its fully bound relaxivity is limited by slow water exchange, as monitored by (1)H NMR relaxometry. This complex interacts weakly with phosphate, but does not form ternary complexes with bidentate bicarbonate and l-lactate anions, indicating that the two inner-sphere water molecules of the [Gd()(H(2)O)(2)](-) complex are not located in adjacent positions in the coordination sphere of the Gd(3+) ion. The transmetallation reaction rate of [Gd()(H(2)O)(2)](-) with Zn(2+) in phosphate buffer solution (pH 7.0) was measured to be similar to that of the backbone unsubstituted [Gd(DTTA-Me)(H(2)O)(2)](-), but twice faster than for [Gd(DTPA-BMA)(H(2)O)]. The in vivo biodistribution studies of the (153)Sm(3+)-labelled ligand () in Wistar rats reveal slow blood elimination and short term fixation in various organs, indicating some dissociation. The bis-hydroxymethyl-substituted DTTA skeleton can be seen as a new lead for the synthesis of high relaxivity contrast agents, although its low thermodynamic and kinetic stability will limit its use to in vitro and animal studies.
Silvério
Sara
S
Centro de Química, Campus de Gualtar, Universidade do Minho, 4710-057 Braga, Portugal.
Torres
Susana
S
Martins
André F
AF
Martins
José A
JA
André
João P
JP
Helm
Lothar
L
Prata
M Isabel M
MI
Santos
Ana C
AC
Geraldes
Carlos F G C
CF
D000818:Animals; D000838:Anions / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D003287:Contrast Media / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D005682:Gadolinium / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D028581:Lanthanoid Series Elements / Q000737:chemistry*; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution; D014867:Water / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
D000838:Anions; D002614:Chelating Agents; D003287:Contrast Media; D028581:Lanthanoid Series Elements; D012709:Serum Albumin; D014867:Water; C060068:diethylenetriaminetetraacetic acid; D004369:Pentetic Acid; D005682:Gadolinium; D015032:Zinc