Relationship of Structure and Brain Uptake between Cu(II)-Dimethylpropylene Imine Phenol and Cu(II)-Dimethylpropylene Amine Phenol

Abstract

Objective: This study was to explore the relationship between the structure and the brain uptake for both of the complexes of Cu(II)-imine phenol and Cu(II)-amine phenol. Methods: The X-ray structures of Cu(II)-dimethylpropylene imine phenol [Cu-DmPn(IP)2] and Cu(II)-dimethylpropylene amine phenol [Cu-DmPn(AP)2] were determined in this laboratory. By reaction of 64Cu(superscript 2+) with both of the ligands under pH 9, 64Cu-DmPn(IP)2 and 64Cu-DmPn(AP)2 were obtained, and were subject to extraction between n-octanol and saline and subsequently the radioactivities in both phases were measured for estimation of the lipophilicities of the two Cu(II) complexes. 64Cu-DmPn(AP)2 was also employed for biodistribution study using male Wistar rates. The similar animal biodistribution of Cu-DmPn(IP)2 was cited from literature. Results: From X-ray crystallography, Cu(II)-dimethylpropylene imine phenol [Cu-DmPn(IP)2] exhibits a mononuclear structure whereas Cu(II)-dimethylpropylene amine phenol [Cu-DmPn(AP)2] exhibits a dinuclear structure. The observed dimeric structure arises from a pair of Cu-ligand chelates expanding their coordination number to five by interaction with one of the phenolic O coordination to the other Cu center. The lipophilicity of Cu-DmPn(IP)2 was much higher than that of Cu-DmPn(AP)2. In the animal trials by rats tracing by radioactive copper, the mononuclear Cu-DmPn(IP)2 was rapidly cleared from the blood and was diffusible across the blood-brain barrier (BBB) into the brain whereas the dinuclear Cu-DmPn(AP)2 was slowly cleared from the circulation and almost not diffusible across the BBB. Conclusion: Cu-DmPn(AP)2 is a dinuclear structure which is much different from the mononuclear structure of Cu-DmPn(IP)2. Cu-DmPn(IP)2 is much higher lipophilic and shows a much higher brain uptake compared to Cu-DmPn(AP)2.