A Bis(pyridine N-oxide) Analogue of DOTA: Relaxometric Properties of the GdIII Complex and Efficient Sensitization of Visible and NIR-Emitting Lanthanide(III) Cations Including PrIII and HoIII

• Published in: Chemistry : a European journal Vol. 20; no. 45; pp. 14834 - 14845
• Main Authors: Martins, André F., Eliseeva, Svetlana V., Carvalho, Henrique F., Teixeira, João M. C., Paula, Carlos T. B., Hermann, Petr, Platas-Iglesias, Carlos, Petoud, Stephane, Tóth, Éva, Geraldes, Carlos F. G. C.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 03-11-2014; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Aqueous solutions; Chemistry; cyclen ligands; imaging agents; lanthanides; Ligands; luminescence; MRI
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201403856

We report the synthesis of a cyclen‐based ligand (4,10‐bis[(1‐oxidopyridin‐2‐yl)methyl]‐1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid=L1) containing two acetate and two 2‐methylpyridine N‐oxide arms anchored on the nitrogen atoms of the cyclen platform, which has been designed for stable complexation of lanthanide(III) ions in aqueous solution. Relaxometric studies suggest that the thermodynamic stability and kinetic inertness of the GdIII complex may be sufficient for biological applications. A detailed structural study of the complexes by 1H NMR spectroscopy and DFT calculations indicates that they adopt an anti‐Δ(λλλλ) conformation in aqueous solution, that is, an anti‐square antiprismatic (anti‐SAP) isomeric form, as demonstrated by analysis of the 1H NMR paramagnetic shifts induced by YbIII. The water‐exchange rate of the GdIII complex is ${k{{298\hfill \atop {\rm ex}\hfill}}}$=6.7×106 s−1, about a quarter of that for the mono‐oxidopyridine analogue, but still about 50 % higher than the ${k{{298\hfill \atop {\rm ex}\hfill}}}$ of GdDOTA (DOTA=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid). The 2‐methylpyridine N‐oxide chromophores can be used to sensitize a wide range of LnIII ions emitting in both the visible (EuIII and TbIII) and NIR (PrIII, NdIII, HoIII, YbIII) spectral regions. The emission quantum yield determined for the YbIII complex (${Q{{{\rm L}\hfill \atop {\rm Yb}\hfill}}}$=7.3(1)×10−3) is among the highest ever reported for complexes of this metal ion in aqueous solution. The sensitization ability of the ligand, together with the spectroscopic and relaxometric properties of its complexes, constitute a useful step forward on the way to efficient dual probes for optical imaging (OI) and MRI.
Dual probes: Stable LnIII complexes of the new cyclen‐based ligand (4,10‐bis[(1‐oxidopyridin‐2‐yl)methyl]‐1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid) adopt an anti‐square antiprismatic conformation in solution (see figure). The pyridine N‐oxide chromophores efficiently sensitize the luminescence of a wide range of LnIII ions emitting in both the visible (EuIII, TbIII) and NIR (PrIII, NdIII, HoIII, YbIII) spectral regions. The relaxometric properties of the GdIII complex suggest that it may serve as an efficient dual probe for optical imaging and MRI.