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Tetradentate imine and amine phenols with an N2O2 donor set can
chelate Cu(II) atom to form the Cu(II) complexes with neutral-
lipophilicity and low molecular weight, being premised to
develop as a cerebral blood flow agent. The main purpose of
this study is to identify the crystal structures, chemical, and
biological characteristics of the Cu(II) imine and amine
phenols. The potential of these Cu(II)-62 complexes has been
evaluated as a clinical tracer for Positron Emission Tomography
(PET). Preliminary characteristics of the Cu(II) complexes with
a series of tetradentate N2O2 ligands, including imine phenols,
have been reported lately. Here we have then focused on crystal
structures of a series of Cu(II) imine phenols. In addition,
because the short half-life of Cu-62 is undesirable for
laboratory research, we have employed longer lived Cu-64 readily
available from the Tsing Hua open pool reactor (THOR), as the
radiocopper in this study. Thirteen Cu(II) imine phenols and
methoxyl-substituted imine phenols with varying lengths of the
alkylenediamine backbone have been prepared and their structures
determined by X-ray diffraction. Most of the Cu(II) imine
phenols studied show four-coordinate, mononuclear, and neutral
complexes with low molecular weights. Elongation of the
alkylenediamine backbone results in the degree of distortion
from square plane, the enlargement of dihedral and N-Cu-N
angles, and the tendency to adopt a mononuclear structure. The
tendency to form H-bonding between the solvent molecule and the
phenol O or the water molecule attached to Cu(II) ion limits the
diffusibility of the Cu(II) imine phenols to cross the cell
membrane. Cu(II) amine phenols are readily formed and are also
neutral-lipophilic. These complexes are less lipophilic than
those with the corresponding Cu(II) imine phenols.
Lipophilicity of the Cu(II) amine phenols is enhanced either by
the addition of methyl groups to the alkylenediamine backbone or
by the alkyl substitution in the bridging carbon atoms. An
alkaline condition to prevent protonation of the amine N atoms
and to facilitate deprotonation of the phenol groups is required
for the coordination of amine phenol ligands to Cu(II) ion. In
solid state, the free ligand exhibits a stretched out, planar
conformation which is significantly distinct from the folded,
dinuclear, square-planar based pyramidal one upon Cu(II)
coordination. In rat biodistribution studies the Cu(II)-64
amine phenols are cleared from the blood rather rapidly and
excreted mainly via hepatobiliary way and partially via urinary
system. Judging from their very low uptake in any particular
organ, none of the Cu(II) complexes studied appears to be
suitable for PET imaging. The very low uptake of Cu(II)-64
amine phenols in the brain cells may be attributed to the H-
bonding formation of phenol O, amine N atoms, and the solvent
molecule attached to Cu(II) ion, as well as the large molecular
weight due to the dinuclear association between Cu(II) and
phenol O atoms.
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