Journal article

Isoquinoline-Based Lanthanide Complexes: Bright NIR Optical Probes and Efficient MRI Agents

In the objective of developing ligands that simultaneously satisfy the requirements for MRI contrast agents and near-IR emitting optical probes that are suitable for imaging, three isoquinoline-based polyaminocarboxylate ligands, L1, L2 and L3, have been synthesized and the corresponding Gd3+, Nd3+ and Yb3+ complexes studied. The specific challenge of the present work was to create NIR emitting agents which (i) have excitation wavelengths compatible with biol. applications and (ii) are able to emit a sufficient no. of photons to ensure sensitive NIR detection for microscopic imaging. Here the authors report the first observation of a NIR signal arising from a Ln3+ complex in aq. soln. in a microscopy setup. The lanthanide complexes have high thermodn. stability (log KLnL =17.7-18.7) and good selectivity for lanthanide ions vs. the endogenous cations Zn2+, Cu2+, and Ca2+ thus preventing transmetalation. A variable temp. and pressure 17O 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 Gd3+ chelates, has been demonstrated by 17O chem. shifts for the Gd3+ complexes and by luminescence lifetime measurements for the Yb3+ analogs. The water exchange on the three Gd3+ complexes is considerably faster (kex298 = (13.9-15.4) × 106 s-1) than on com. Gd3+-based contrast agents and proceeds via a dissociative mechanism, as evidenced by the large pos. activation vols. for GdL1 and GdL2 (+10.3 ± 0.9 and +10.6 ± 0.9 cm3 mol-1, resp.). The relaxivity of GdL1 is doubled at 40 MHz and 298 K in fetal bovine serum (r1 = 16.1 vs. 8.5 mM-1 s-1 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 analogs and provides significant shifts of the excitation energies toward lower values which therefore become more adapted for biol. applications. L2 and L3 bear two methoxy substituents on the arom. core in ortho and para positions, resp., that further modulate their electronic structure. The Nd3+ and Yb3+ complexes of the ligand L3, which incorporates the p-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 analog. The luminescence quantum yields of the Nd3+ (0.013-0.016%) and Yb3+ chelates (0.028-0.040%) are in the range of the best nonhydrated complexes, despite the presence of two inner sphere water mols. More importantly, the 980 nm NIR emission band of YbL3 was detected with a good sensitivity in a proof of concept microscopy expt. at a concn. of 10 μM in fetal bovine serum. The authors' results demonstrate that even bishydrated NIR lanthanide complexes can emit a sufficient no. of photons to ensure sensitive detection in practical applications. In particular, these ligands contg. an arom. 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 Gd3+ analogs. They constitute a highly versatile platform for the development of bimodal MR and optical imaging probes based on a simple mixt. of Gd3+ and Yb3+/Nd3+ complexes using an identical chelator. Given the presence of two inner sphere water mols., important for MRI applications of the corresponding Gd3+ analogs, this result is particularly exciting and opens wide perspectives not only for NIR imaging based on Ln3+ ions but also for the design of combined NIR optical and MRI probes.


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