Polyamine-substituted Gd-DTPA: intracellular, tumor-selective, high-retention MRI contrast agents

W. E. Hull, M. Wolf, S. Heiland, U. Bauder-Wuest, M. Eisenhut Central Spectroscopy, German Cancer Research Center (DKFZ), Heidelberg, Germany, Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany, Experimental Neuroradiology, University of Heidelberg, Heidelberg, Germany Introduction Conventional paramagnetic MRI contrast agents such as [Gd(DTPA)(H2O)] 2– (Magnevist) exhibit low tissue specificity. Therefore, increasing efforts are being made to develop targeted agents [1] through conjugation with monoclonal antibodies [2] or modification to achieve high affinity for a tumor-specific cell-surface protein, for example [3]. An alternative strategy is to employ intracellular uptake to “label” the cells of interest. This requires, for detectable T1-weighted MRI contrast, internalization of 10 7 10 Gd(III) complexes (0.017 0.17 fmol) per cell. However, clinical contrast agents do not readily enter cells passively or via active transport. It has been shown that ligand sidechains containing alkylamine or polyamine moieties enhance the intracellular uptake of technetium complexes or radioiodinated benzamides for melanoma scintigraphy [4,5], presumably by active transport via polyamine transporter proteins. Since proliferating tumor cells are expected to have enhanced polyamine uptake, our strategy was to develop a new class of polyamine-derivatized Gd-DTPA complexes with high intracellular tumor uptake and retention.