Comparison of MRI properties between derivatized DTPA and DOTA gadolinium-dendrimer conjugates

Abstract

In this report we directly compare the in vivo and in vitro MRI properties of gadolinium-dendrimer conjugates of derivatized acyclic diethylenetriamine-N,N',N',N'',N''-pentaacetic acid (1B4M-DTPA) and macrocyclic 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (C-DOTA). The metal-ligand chelates were pre-formed in alcohol prior to conjugation to the generation 4 PAMAM dendrimer (G4D), and the dendrimer-based agents were purified by Sephadex(R) G-25 column. The analysis and SE-HPLC data indicated chelate to dendrimer ratios of 30:1 and 28:1, respectively. Molar relaxivity measured at pH 7.4, 22 degrees C, and 3T are comparable (29.5 vs 26.9 mM(-1)s(-1)), and both conjugates are equally viable as MRI contrast agents based on the images obtained. The macrocyclic agent however exhibits a faster rate of clearance in vivo (t(1/2)=16 vs 29 min). Our conclusion is that the macrocyclic-based agent is the more suitable agent for in vivo use for these reasons combined with kinetic inertness associated with the Gd(III) DOTA complex stability properties.

Figure 1

Synthetic scheme for G4-(C-DOTA-Gd)₂₈ conjugate.

Figure 2

Molar relaxivity plots of G4-(C-DOTA-Gd)₂₈ (▲; 29.5 mM⁻¹s⁻¹), G4-(1B4M-DTPA-Gd)₃₀ (■; 26.9 mM⁻¹s⁻¹) and Magnevist (♦; 4.2 mM⁻¹s⁻¹).

Figure 3

Average blood clearance rates measured at the jugular vein of G4-(1B4M-DTPA-Gd)₃₀ and G4-(C-DOTA-Gd)₂₈.

Figure 4

Dynamic MRI of mice injected with 0.015 mmol/Kg of G4-(C-DOTA-Gd)₂₈ (above) and G4-(1B4M-DTPAGd)₃₀ (below). All images were acquired at 16–23 min post-injection.

Figure 4

Dynamic MRI of mice injected with 0.015 mmol/Kg of G4-(C-DOTA-Gd)₂₈ (above) and G4-(1B4M-DTPAGd)₃₀ (below). All images were acquired at 16–23 min post-injection.

Figure 5

MR images of the left kidney obtained prior to injection of agents (a) and 20 min after injection of G4-(1B4M-DTPA-Gd)₃₀ (b) and G4-(C-DOTA-Gd)₂₈ (c).

Figure 6

Structures of (C-DOTA-Gd)⁻¹ (left) vs. (1B4M-DTPA-Gd)⁻² (right).