Toward improved syntheses of dendrimer-based magnetic resonance imaging contrast agents: new bifunctional diethylenetriaminepentaacetic acid ligands and nonaqueous conjugation chemistry.
Two different fourth-generation (G4) polyaminonamido dendrimer-based magnetic resonsance (MR) agents were prepared by a new synthetic approach wherein tert-butyl-protected forms of 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriamine pentaacetic acid (1B4M-DTPA), bearing either an isothiocyanate or a succinimidyl ester moiety, respectively, were conjugated to the primary amines of the dendrimer. Purification was facilitated using a solid phase, N-(2-aminoethyl)aminomethyl polystyrene. After Gd(III) incorporation, molar relaxivity measurements of both new dendrimer-based agents as compared to a G4 agent prepared by an aqueous chemistry route indicated no significant changes in relaxivity. Comparative MR imaging revealed equivalent enhancement of the vessels and organs such as the kidney and liver, although slightly different vascular clearance rates were observed. This general synthesis provides a procedure for preparation of dendrimer-based MR agents for clinical applications with higher yields and efficiency while enhancing versatility. The latter aspect is further demonstrated by preparation of a novel maleimide analog of 1B4M-DTPA from a key synthetic intermediate aniline derivative.
Xu
Heng
H
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892-1088, USA.
Regino
Celeste A S
CA
Bernardo
Marcelino
M
Koyama
Yoshinori
Y
Kobayashi
Hisataka
H
Choyke
Peter L
PL
Brechbiel
Martin W
MW
D000818:Animals; D003287:Contrast Media; D050091:Dendrimers / Q000737:chemistry*; D005260:Female; D008024:Ligands; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D004369:Pentetic Acid / Q000138:chemical synthesis* / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D003287:Contrast Media; D050091:Dendrimers; D008024:Ligands; D004369:Pentetic Acid