posted on 2021-07-23, 17:44authored byNishanth
D. Tirukoti, Liat Avram, Talia Haris, Benjamin Lerner, Yael Diskin-Posner, Hyla Allouche-Arnon, Amnon Bar-Shir
Fast ion-chelate
dissociation rates and weak ion-chelate affinities
are desired kinetic and thermodynamic features for imaging probes
to allow reversible binding and to prevent deviation from basal ionic
levels. Nevertheless, such properties often result in poor readouts
upon ion binding, frequently result in low ion specificity, and do
not allow the detection of a wide range of concentrations. Herein,
we show the design, synthesis, characterization, and implementation
of a Zn2+-probe developed for MRI that possesses reversible
Zn2+-binding properties with a rapid dissociation rate
(koff = 845 ± 35 s–1) for the detection of a wide range of biologically relevant concentrations.
Benefiting from the implementation of chemical exchange saturation
transfer (CEST), which is here applied in the 19F-MRI framework
in an approach termed ion CEST (iCEST), we demonstrate the ability
to map labile Zn2+ with spectrally resolved specificity
and with no interference from competitive cations. Relying on fast koff rates for enhanced signal amplification,
the use of iCEST allowed the designed fluorinated chelate to experience
weak Zn2+-binding affinity (Kd at the mM range), but without compromising high cationic specificity,
which is demonstrated here for mapping the distribution of labile
Zn2+ in the hippocampal tissue of a live mouse. This strategy
for accelerating ion-chelate koff rates
for the enhancement of MRI signal amplifications without affecting
ion specificity could open new avenues for the design of additional
probes for other metal ions beyond zinc.