Evaluation of the H2dedpa Scaffold and its cRGDyK Conjugates for Labeling with 64Cu

Studies of the acyclic ligand scaffold H(2)dedpa and its derivatives with the peptide cRGDyK for application in copper radiopharmaceuticals are described. Previously shown to be a superb ligand for (67/68)Ga, the chelate is now shown to coordinate (64)Cu in its derivatized and nonderivatized forms rapidly under mild reaction conditions (10 min, RT, pH 5.5 10 mM sodium acetate buffered solution). The hexadentate, distorted octahedral coordination of H(2)dedpa is confirmed in the corresponding solid state X-ray crystal structure of [Cu(dedpa)]. Cyclic voltammetry determined the reduction potential of [Cu(dedpa)] to be below values found for common bioreductants. Reduction and reoxidation were irreversible but reproducible, indicating a potential change of coordination mode upon reduction of Cu(II) to Cu(I). The thermodynamic stability constant log K(CuL) was determined to be 19.16(5), comparable to other frequently used (64)Cu chelates. Serum stability of the (64)Cu labeled chelate revealed only 3% transchelation/association to serum proteins after 2 h, while the conjugates reveal 10% ([Cu(RGD1)]) and 6% ([Cu(RGD2)]) transchelation at the same time point.