Synthesis and relaxometry of high-generation (G = 5, 7, 9, and 10) PAMAM dendrimer-DOTA-gadolinium chelates

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Abstract
A series of high‐generation (G) ethylenediamine‐core polyamidoamine (PAMAM) dendrimers corresponding to G = 5, 7, 9, and 10 were conjugated with the bifunctional chelate 2‐(4‐isothiocyanatobenzyl)‐1,4,7,10‐tetraazacyclododecane‐N,N′,N”,N”'‐tetraacetate (p‐SCN‐Bz‐DOTA). Gadolinium (III) ion was added to the macromolecules, and the 1/T1 and 1/T2 NMRD profiles were measured at 3°, 23°, and 37°C. The synthesis resulted in preparations that ranged from an average of 127 chelates and 96 Gd3+ ions per G = 5 dendrimer to an average of 3727 chelates and1860 Gd3+ ions per G = 10 dendrimer. At 20 MHz and 23°C, the 1/T1 ion relaxivity increased from 30 mM‐1s ‐1 for the G = 5 to 35 mM‐1 s‐1 for the G = 7 PAMAM dendrimer‐DOTA‐Gd, reaching a plateau at 36 mM‐1 s‐1 for the G = 9 and G = 10 dendrimers. A similar plateau was observed for 1/T2 with values of 36 mM‐1 s‐1 for G = 5, 42 mM‐1 s‐1 for G = 7, and 45 mM‐1 s‐1 for the G = 9 and G = 10 dendrimers. This “saturation” of ion relaxivity for high‐generation dendrimers occurred over the entire frequency range studied. The 1/T1 and 1/T2 relaxivities decreased as the temperature decreased for each generation of dendrimer studied, implying that slow water exchange of bound water molecules with the bulk solvent limits the relaxivity. In such circumstances, increases in the rotational correlation time of the macromolecules associated with higher generations of dendrimer does not result in significant increases in the ion relaxivity. Although the ion relaxivity does not increase, the total molecular relaxivities increased from 2880 mM‐1 s‐1 to 66960 mM‐1 s‐1 for the G = 5 to the G = 10 dendrimer. The current findings are relevant for the design of high‐generation dendrimer‐based receptor agents. J. Magn. Reson. Imaging 1999; 9:348–352.

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