Modification of Biodistribution and Brain Uptake of Copper Bis(thiosemicarbazonato) Complexes by the Incorporation of Amine and Polyamine Functional Groups

• Published in: Inorganic chemistry 2019-04, Vol.58 (7), p.4540-4552
• Main Authors: Paterson, Brett M, Cullinane, Carleen, Crouch, Peter J, White, Anthony R, Barnham, Kevin J, Roselt, Peter D, Noonan, Wayne, Binns, David, Hicks, Rodney J, Donnelly, Paul S
• Format: Article
• Language: English
• Subjects: Animals; Brain - metabolism; Cell Line, Tumor; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacokinetics; Copper Radioisotopes - chemistry; Female; Humans; Ligands; Mice, Inbred BALB C; Polyamines - chemical synthesis; Polyamines - chemistry; Polyamines - pharmacokinetics; Positron-Emission Tomography; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacokinetics; Tissue Distribution
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/acs.inorgchem.9b00117

The synthesis of new bis­(thiosemicarbazonato)­copper­(II) complexes featuring polyamine substituents via selective transamination reactions is presented. Polyamines of different lengths, with different ionizable substituent groups, were used to modify and adjust the hydrophilic/lipophilic balance of the copper complexes. The new analogues were radiolabeled with copper-64 and their lipophilicities estimated using distribution coefficients. The cell uptake of the new polyamine complexes was investigated with preliminary in vitro biological studies using a neuroblastoma cancer cell line. The in vivo biodistribution of three of the new analogues was investigated in vivo in mice using positron-emission tomography imaging, and one of the new complexes was compared to [64Cu]­Cu­(atsm) in an A431 squamous cell carcinoma xenograft model. Modification of the copper complexes with various amine-containing functional groups alters the biodistribution of the complexes in mice. One complex, with a pendent (N,N-dimethylamino)­ethane functional group, displayed tumor uptake similar to that of [64Cu]­Cu­(atsm) but higher brain uptake, suggesting that this compound has the potential to be of use in the diagnostic brain imaging of tumors and neurodegenerative diseases.