Synthesis and characterization of the tetraazamacrocycle 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (H2Me2DO2A) and of its neutral copper(II) complex [Cu(Me2DO2A)].: A new 64Cu-labeled macrocyclic complex for positron emission tomography imaging

The new macrocycle 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (H(2)Me(2)DO2A, H2L) has been synthesized and characterized. The basicity constants of the macrocycle and the stability constants of its complex formation with copper(II) ions have been determined in aqueous solution by potentiometry. The protonation sequence of the macrocycle has been studied by H-1 and C-13-{H-1} NMR spectroscopy. The data obtained are consistent with the first and second protonations taking place at the methyl-substituted nitrogen atoms, while the third and fourth protonations involve the two carboxylate arms. High-resolution NMR studies have revealed that the ethylenic protons in the tetraprotonated H4L2+ species are inequivalent due to multiple hydrogen bonds within the macrocycle ring, indicating that the system is locked in a rigid conformation on the NMR timescale. The molecular structure of the copper(II) complex [Cu(Me(2)DO2A)]. 2H(2)O has been determined by a single crystal X-ray analysis. The macrocycle wraps the metal in a distorted octahedral geometry using the four nitrogen atoms and two oxygen atoms from the two carboxylate groups. These latter are cis to each other. The excellent stability of [Cu(Me(2)DO2A)] at physiological pH is confirmed by a cyclic voltammetry study that shows the complex to be irreversibly reduced at E-p=-0.81 V. The radioactive Cu-64-labeled complex [Cu-64(Me(2)DO2A)] has been synthesized using (CuCl2)-Cu-64. Animal biodistribution studies have been performed by bolus injection in rabbit and followed by Positron Emission Tomography (PET), an in vivo imaging technique used in nuclear medicine to detect the regional distribution and concentration of positron emitting radionuclides. PET images showed that the tested compound has high uptake in liver, kidneys and bladder. A significant uptake of radioactivity is observed in brain.