Thanks
to their versatile magnetic and luminescence features, lanthanide
complexes have gained a central position in biomedical imaging as
magnetic resonance imaging (MRI) contrast agents and optical imaging
probes. In addition, appropriate chemical design allows modification
of the magnetic relaxation properties of GdIII complexes
and the optical properties of visible- or near-infrared (NIR)-emitting
lanthanide chelates upon interaction with various biomarkers, which
makes them ideal candidates for the creation of responsive agents.
In this Forum Article, we demonstrate such design principles as well
as the difficulties encountered in the context of neurotransmitter
(NT) detection. Lanthanide(III) complexes of a macrocyclic ligand
incorporating a benzophenone chromophore and a monoazacrown ether
(LnL
3
) have been synthesized
as responsive probes to monitor amino acid NTs either in MRI (Ln =
Gd) or in NIR optical detection (Ln = Nd or Yb). The parameters characterizing
the water exchange and rotational dynamics of the gadolinium(III)
complex were assessed by 17O NMR and 1H NMRD.
In the presence of zwitterionic NTs, the inner-sphere water molecule
is replaced by the carboxylate function of the NTs in the gadolinium(III)
complex, leading to a decrease of the longitudinal relaxivity from
6.7 to 2–2.5 mM–1 s–1 (300
MHz and 37 °C). The apparent affinity constants range from K
a = 35 for γ-aminobutyric acid (GABA)
to 80 M–1 for glycine and glutamate, and there is
no selectivity with respect to hydrogen carbonate (K
a = 232; pH 7.4). The gadolinium(III) complex interacts
with human serum albumin (HSA), resulting in a 60% increase in the
relaxivity (20 MHz, 37 °C) in the absence of NTs. The HSA-bound
complex, however, was revealed to be less responsive to NTs because
of displacement of the GdIII-bound water by HSA, which
was confirmed by the hydration number calculated from luminescence
lifetimes of the HSA-bound europium(III) complex. The creation of
an imaging agent suitable for NIR detection of NTs for an enhanced
sensitivity in biological systems using the benzophenone (BP) moiety
as the sensitizer of lanthanide luminescence was also attempted. Upon
excitation at 300 nm of the BP chromophore in aqueous solutions of
NdL
3
and YbL
3
, characteristic NIR emissions of NdIII and YbIII were observed because of 4F3/2 → 4I
J
(J = 9/2–13/2) and 2F5/2 → 2F7/2 transitions, respectively, indicating that this chromophore
is a suitable antenna. Despite these promising results, luminescence
titrations of NdIII and YbIII complexes with
NTs were not conclusive because of chemical conversion of the ligand
triggered by light, preventing quantitative analysis. The observed
photochemical reaction of the ligand is strongly dependent on the
nature of the lanthanide chelated; it is considerably slowed down
in the presence of NdIII and EuIII.