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

The present study describes the synthesis of Cu(II) and radioactive ^67.64Cu(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 ^67,64Cu-radiolabeled complexes, [Cu(tachpyr)]²⁺ and [Cu(tach-6-Me-pyr)]²⁺, occurs in aqueous (0.15 M NH₄OAc 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 away from copper in [Cu(tach-6-Mepyr)]²⁺, resulting in a highly distorted trigonal-bipyramidal coordination geometry. The solid-state structures of the complexes correlate well with their stabilities in human serum at 37 °C. Thus, [⁶⁷Cu(tachpyr)]²⁺ possesses excellent stability, being unchanged after a period of 7 days, while [⁶⁷Cu(tach-6-Mepyr)]²⁺ decomposes within 1 h. Tachpyr may be an excellent candidate for developing new Cu(II) radiopharmaceuticals for diagnosis and therapy.