DYSPROSIUM-DOTA-PAMAM DENDRIMERS AS MACROMOLECULAR T2 CONTRAST AGENTS- PREPARATION AND RELAXOMETRY

RATIONALE AND OBJECTIVES. The authors have investigated dysprosium [Dy ]-DOTA-PAMAM, generation 5 (G=5) dendrimers as a possible new class of macromolecular T2 contrast agents. The use of DOTA provides a metal c omplex with greater stability than can be achieved using DTPA as ligan d, an important factor in the design of blood pool agents with long ha lf-lives. METHODS. Generation 5 ammonia-core PAMAM dendrimers were lin ked to the bifunctional ligand p-SCN-Bz-DOTA, After determination of t he number of conjugated DOTA molecules by H-1 nuclear magnetic resonan ce, Dy3+ was titrated at a 90% molar ratio. For comparison, single ion ic chelates of Dy-DTPA and Dy-DOTA also were prepared. Using a variabl e field relaxometer, T1 and T2 relaxation times mere measured at 13 di fferent held strengths from 0.05 to 1.5 T and temperatures of 3, 10, 2 0 and 37 degrees C. RESULTS. The synthesis resulted in a preparation w ith 76 DOTA and 68 Dy3+ ions per dendrimer molecule, The T1 relaxivity values for Dy-DTPA, Dy-DOTA, and the Dy-DOTA-based dendrimer all were independent of field strength, with values between 0.12 and 0.20 mM(- 1)sec(-1). At lower fields (0.05-0.1 T), 1/T2 was identical to 1/T1, A t higher fields, however, 1/T2 increased quadratically with field stre ngth, with a strong dependence on temperature, The field-dependent com ponent of 1/T2 was up to three times higher for the Dy-DOTA-based dend rimer compared with the single chelate molecules, with coefficients of 0.37 to 0.03 sec(-1)/Tesla(2) for T = 3 to 37 degrees C. CONCLUSIONS. The results are interpreted with the ''inner sphere'' theory of susce ptibility effects (Curie spin relaxation). The large temperature depen dence suggests that the dominant mechanism of relaxation is the contac t interaction effect, with the proton residence time as the primary ti me constant, This largely unexplored relaxation mechanism has the pote ntial to create a new class of T2-selective contrast agents.