Isoquinoline-Based Lanthanide
Complexes: Bright NIR Optical Probes and Efficient MRI Agents
- Publication date
- Publisher
Abstract
In the objective of developing ligands that simultaneously
satisfy the requirements for MRI contrast agents and near-infrared
emitting optical probes that are suitable for imaging, three isoquinoline-based
polyaminocarboxylate ligands, <b>L1</b>, <b>L2</b> and <b>L3</b>, have been synthesized and the corresponding Gd<sup>3+</sup>, Nd<sup>3+</sup> and Yb<sup>3+</sup> complexes investigated. The
specific challenge of the present work was to create NIR emitting
agents which (i) have excitation wavelengths compatible with biological
applications and (ii) are able to emit a sufficient number of photons
to ensure sensitive NIR detection for microscopic imaging. Here we
report the first observation of a NIR signal arising from a Ln<sup>3+</sup> complex in aqueous solution in a microscopy setup. The lanthanide
complexes have high thermodynamic stability (log <i>K</i><sub>LnL</sub> =17.7–18.7) and good selectivity for lanthanide
ions versus the endogenous cations Zn<sup>2+</sup>, Cu<sup>2+</sup>, and Ca<sup>2+</sup> thus preventing transmetalation. A variable
temperature and pressure <sup>17</sup>O NMR study combined with nuclear
magnetic relaxation dispersion measurements yielded the microscopic
parameters characterizing water exchange and rotation. Bishydration
of the lanthanide cation in the complexes, an important advantage
to obtain high relaxivity for the Gd<sup>3+</sup> chelates, has been
demonstrated by <sup>17</sup>O chemical shifts for the Gd<sup>3+</sup> complexes and by luminescence lifetime measurements for the Yb<sup>3+</sup> analogues. The water exchange on the three Gd<sup>3+</sup> complexes is considerably faster (<i>k</i><sub>ex</sub><sup>298</sup> = (13.9–15.4) × 10<sup>6</sup> s<sup>–1</sup>) than on commercial Gd<sup>3+</sup>-based contrast agents and proceeds <i>via</i> a dissociative mechanism, as evidenced by the large
positive activation volumes for Gd<b>L1</b> and Gd<b>L2</b> (+10.3 ± 0.9 and +10.6 ± 0.9 cm<sup>3</sup> mol<sup>–1</sup>, respectively). The relaxivity of Gd<b>L1</b> is doubled at
40 MHz and 298 K in fetal bovine serum (<i>r</i><sub>1</sub> = 16.1 vs 8.5 mM<sup>–1</sup> s<sup>–1</sup> in HEPES
buffer), due to hydrophobic interactions between the chelate and serum
proteins. The isoquinoline core allows for the optimization of the
optical properties of the luminescent lanthanide complexes in comparison
to the pyridinic analogues and provides significant shifts of the
excitation energies toward lower values which therefore become more
adapted for biological applications. <b>L2</b> and <b>L3</b> bear two methoxy substituents on the aromatic core in ortho and
para positions, respectively, that further modulate their electronic
structure. The Nd<sup>3+</sup> and Yb<sup>3+</sup> complexes of the
ligand <b>L3</b>, which incorporates the <i>p</i>-dimethoxyisoquinoline
moiety, can be excited up to 420 nm. This wavelength is shifted over
100 nm toward lower energy in comparison to the pyridine-based analogue.
The luminescence quantum yields of the Nd<sup>3+</sup> (0.013–0.016%)
and Yb<sup>3+</sup> chelates (0.028–0.040%) are in the range
of the best nonhydrated complexes, despite the presence of two inner
sphere water molecules. More importantly, the 980 nm NIR emission
band of Yb<b>L3</b> was detected with a good sensitivity in
a proof of concept microscopy experiment at a concentration of 10
μM in fetal bovine serum. Our results demonstrate that even
bishydrated NIR lanthanide complexes can emit a sufficient number
of photons to ensure sensitive detection in practical applications.
In particular, these ligands containing an aromatic core with coordinating
pyridine nitrogen can be easily modified to tune the optical properties
of the NIR luminescent lanthanide complexes while retaining good complex
stability and MRI characteristics for the Gd<sup>3+</sup> analogues.
They constitute a highly versatile platform for the development of
bimodal MR and optical imaging probes based on a simple mixture of
Gd<sup>3+</sup> and Yb<sup>3+</sup>/Nd<sup>3+</sup> complexes using
an identical chelator. Given the presence of two inner sphere water
molecules, important for MRI applications of the corresponding Gd<sup>3+</sup> analogues, this result is particularly exciting and opens
wide perspectives not only for NIR imaging based on Ln<sup>3+</sup> ions but also for the design of combined NIR optical and MRI probes