Dendrimer‐based metal chelates: A new class of magnetic resonance imaging contrast agents

TLDR

The agents are synthesized by conjugating free amines of polyamidoamine Starburs™ dendrimers to the chelator 2‑(4‑isothiocyanatobenzyl)‑6‑methyl‑diethylenetriaminepenta‑acetic acid. The dendrimer‑gadolinium poly‑chelates exhibit up to six‑fold higher relaxivity per Gd(III) ion than Gd‑DTPA, with one construct binding 170 Gd ions and achieving a molecular relaxivity of 5,800 mM⁻¹ s⁻¹, and they markedly enhance conventional MR images and 3D TOF angiograms with half‑lives of 40 ± 10 min and 200 ± 100 min—over twice the 24 ± 4 min of Gd‑DTPA—suggesting broad clinical utility.

Abstract

Abstract We have developed a new class of magnetic resonance imaging contrast agents with large proton relaxation enhancements and high molecular relaxivities. The reagents are built from the polyamidoamine form of Starburs™ dendrimers in which free amines have been conjugated to the chelator 2‐(4‐isothiocyanatobnenzyl)‐6‐methyl‐diethylenetriaminepenta‐acetic acid. The dendrimer gadolinium poly‐chelates have enhancement factors, i.e., the ratlo of the relaxivity per Gd(III) ion to that of Gd(III)‐diethylenetriaminepentaacetic acid, of up to 6. These factors are more than twice those observed for analogous metal‐chelate conjugates formed with serum albumins, polylysine, or dextran. One of the dendrimer‐metal chelate conjugates has 170 gadolinium ions bound, which greatly exceeds the number bound to other macromolecular agents reported In the literature, and has a molecular relaxivity of 5,800 (m M · s) −1 , at 25 MHz, 20°C, and pH of 7.4. We observed that these dendrimer‐based agents enhance conventional MR images and 3D time of flight MR angiograms, and that those with molecular weights of 8,508 and 139,000 g/mole have enhancement half lives of 40 ± 10 and 200 ± 100 min, much longer than the 24 ± 4 min measured for Gd(III)‐diethylenetriaminepentaacetic acid. Our results suggest that this new and powerful class of contrast agents have the potential for diverse and extensive application in MR imaging.