Novel chelating agents for potential clinical applications of copper

Abstract Copper offers a unique selection of radioisotopes ( 60 Cu, 61 Cu, 62 Cu, 64 Cu, and 67 Cu) with half-lives ranging from 9.8 min to 61.9 h suitable for imaging and/or radiotherapy. In peptide/antibody targeted radiotherapy one of the most studied chelating agents for copper, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), has been employed in clinical trials, but transchelation to ceruloplasmin and/or superoxide dismutase in vivo has been noted. In this study, a series of novel hexadentate chelating agents based on N,N′,N″ -tris(2-pyridylmethyl)-1,3,5- cis,cis ,-triaminocyclohexane (tachpyr) have been synthesized and the serum stability of their copper complexes was evaluated as compared to TETA. Copper complexes of tachpyr modified at the 3, 4, or 5 position or with replacement of pyridine by imidazole have serum stability comparable to Cu[TETA]. When the complexes were cross-challenged, Cu[TETA] versus tachpyr or 1,3,5- cis,cis ,-triaminocyclohexane- N,N′,N″ -tris-(2-methyl-( N -methylimidazole)) (IM), tachpyr and IM appear to have superior copper chelation ability to TETA. When challenged by a large excess of non-radioactive copper, copper exchange with the tachpyr radio-copper complex was observed. However, tachpyr clearly exhibited a significant preference for Cu(II) over Zn(II) or Fe(III). Therefore, tachpyr, 1,3,5- cis,cis ,-triaminocyclohexane- N,N′,N″ -tri-(3-methyl-2-methylpyridineimine) (tachpyr(3-Me)), 1,3,5- cis,cis ,-triaminocyclohexane- N,N′,N″ -tri-(4-methyl-2-methylpyridineimine) (tachpyr(4-Me)), 1,3,5- cis,cis ,-triaminocyclohexane- N,N′,N″ -tri-(5-methyl-2-methylpyridineimine) (tachpyr(5-Me)) and IM easily form copper complexes with high stability. These novel chelating agents provide an attractive lead for creation of new copper radiopharmaceuticals for diagnosis and therapy applications.