Synthesis of novel 1,3,5-cis, cis-triaminocyclohexane ligands based Cu(II) complexes as potential radiopharmaceuticals and correlation of structure and serum stability

摘要

The present study describes the synthesis of Cu(II) and radioactive ~(67, 64)Cu(II) complexes with N,N',N"-tris(2-pyridylmethyl)-1,3,5-cis, cis-triaminocyclohexane (tachpyr) and a new pyridyl ring alkylated derivative, N,N',N"-tris(6-methyl-2-pyridylmethyl)-1,3,5-cis, cis-triaminocyclohexane (tach-6-Me-pyr) and the investigation of their structural and solution properties as well as stability in human serum. Facile formation of both the 'cold' and ~(67,64)Cu-radiolabeled complexes, [Cu(tachpyr)]~(2+) and [Cu(tach-6-Me-pyr)]~(2+), occurs in aqueous (0.15 M NH_4OAc buffer, pH 6.5) or methanolic solvent. X-ray crystallography reveals that Cu(II) is hexacoordinate in [Cu(tachpyr)]~(2+) while methylation at the 6-position of the pyridyl donors in tachpyr produces considerable steric hindrance. Thus one pyridyl arm of tach-=6-Mepyr is rotated entirely wasy from copper in [Cu(tach-6-Mepyr)]~(2+), resulting in a highly distorted trigonal-bipyramidal coordination geometry. The solid-state structure of the complexes correlate well with their stabilities in human serum at 37 deg C. Thus, [~(67)Cu(tachpyr)]~(2+) possesses excellent stability, being unchanged after a period of 7 days, while [~(67)Cu(tach-6-Mepyr)]~(2+) decomposes within 1 h. Tachpyr may be an excellent candidate for developing new Cu(II) radiopharmaceuticals for diagnosis and therapy.