Protonation of a distant, noncoordinated
group of metal-based magnetic resonance imaging contrast agents potentially
changes their relaxivity. The effect of a positive charge of the drug
on the human serum albumin (HSA)–drug interaction remains poorly
understood as well. Accordingly, a (dibenzylamino)methylphosphinate
derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid (DOTA) was efficiently synthesized using pyridine as the solvent
for a Mannich-type reaction of tBu3DO3A,
formaldehyde, and Bn2NCH2PO2H2 ethyl ester. The ligand protonation and metal ion (Gd3+, Cu2+, and Zn2+) stability constants
were similar to those of the parent DOTA, whereas the basicity of
the side-chain amino group of the complexes (logK
A = 5.8) was 1 order of magnitude lower than that of the
free ligand (log K
A = 6.8). The presence
of one bound water molecule in both deprotonated and protonated forms
of the gadolinium(III) complex was deduced from the solid-state X-ray
diffraction data [gadolinium(III) and dysprosium(III)], from the square
antiprism/twisted square antiprism (SA/TSA) isomer ratio along the
lanthanide series, from the fluorescence data of the europium(III)
complex, and from the 17O NMR measurements of the dysprosium(III)
and gadolinium(III) complexes. In the gadolinium(III) complex with
the deprotonated amino group, water exchange is extremely fast (τM = 6 ns at 25 °C), most likely thanks to the high abundance
of the TSA isomer and to the presence of a proximate protonable group,
which assists the water-exchange process. The interaction between
lanthanide(III) complexes and HSA is pH-dependent, and the deprotonated
form is bound much more efficaciously (∼13% and ∼70%
bound complex at pH = 4 and 7, respectively). The relaxivities of
the complex and its HSA adduct are also pH-dependent, and the latter
is approximately 2–3 times increased at pH = 4–7. The
relaxivity for the supramolecular HSA–complex adduct (r
1
b) is as high as 52 mM–1 s–1 at neutral pH (at 20 MHz and 25 °C).
The findings of this study stand as a proof-of-concept, showing the
ability to manipulate an albumin–drug interaction, and thus
the blood pool residence time of the drug, by introducing a positive
charge in a side-chain amino group.
