Understanding the optical and magnetic properties of ytterbium(III) complexes

The absorption and emission spectra of three Yb3+ complexes possessing D3, D2 and C2 symmetries were analyzed with the aid of ab initio calculations based on Complete Active Space Self-Consistent Field (CASSCF) wave functions (CAS(13,7)). The absorption spectra present contributions from both cold and hot bands, involving thermally populated excited sublevels of the 2 F7/2 manifold. The high-resolution emission spectrum of the tris-picolinate complex [Yb(DPA)3] 3- recorded at 77 K presents four components, while the complexes with macrocyclic ligands show both cold and hot emission bands, resulting in more than four components for the 2 F5/2→2 F7/2 transition. The combined information provided by the absorption and emission spectra allowed to identify most of the crystal field sublevels of the 2 F5/2 and 2 F7/2 states. The energies of these crystal field components are well reproduced by the ab initio calculations, with deviations typically lower than 100 cm-1. The crystal field splitting is very sensitive to subtle changes of the Yb3+ coordination environment. The magnetic anisotropy of [Yb(DPA)3] 3- obtained with ab initio calculations was found to be extremely sensitive to changes in the twist angle of the upper and lower faces of the tricapped trigonal prismatic coordination polyhedron. Ab initio ligand field theory (AILFT) provides a straightforward chemical justification for the changes in magnetic anisotropy, which are responsible for the observed pseudocontact shifts in the NMR spectra.Agencia Estatal de Investigación | Ref. CTQ2016-76756-PXunta de Galicia | Ref. ED431B 2017/59Xunta de Galicia | Ref. ED431D 2017/01Deutsche Forschungsgemeinschaft | Ref. SE 1448/6-1Deutsche Forschungsgemeinschaft | Ref. SE 1448/8-1Eberhard Karls Universität Tübingen | Ref. ZUK 6

Lanthanide complexes with 1 H paraCEST and 19 F response for magnetic resonance imaging applications

We present a detailed study of the lanthanide(III) complexes with cyclen-based ligands containing phenylacetamide pen-dants that incorporate CF3 group(s) at different distances from the metal ion. The complexes exhibit square antiprismatic (SAP) coordination in solution, as demonstrated by the analysis of the Yb3+ induced paramagnetic shifts and the X ray structure of the [YbL3] complex. Luminescence lifetime measurements and a detailed 1H and 17O relaxometric characteriza-tion confirmed the presence of an inner-sphere water molecule. The Tm3+ complexes provide Chemical Exchange Satura-tion Transfer (CEST) response upon saturation at the frequency of the amide protons. A 19F relaxation study provided accu-rate estimates of the Ln···F distances that were used to rationalize the efficiency of the complexes as 19F MRI probes, which was tested in vitro using MRI phantom studies.Agencia Estatal de Investigación | Ref. CTQ2016-76756-PXunta de Galicia | Ref. Ref. ED431B 2017/59Xunta de Galicia | Ref. ED431D 2017/01Ministerio de Economía y Competitividad | Ref. BES-2014-068399Ministerio de Economía y Competitividad | Ref. EEBB-I-17-12213Ministerio de Economía y Competitividad | Ref. EEBB-I-18-13075Universitá degli Studi del Piemonte Oriental

Stable and inert macrocyclic cobalt(ii) and nickel(ii) complexes with paraCEST response

We report the synthesis of the macrocyclic ligands 3,9 PC2AMH (2,2’-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,9-diyl)diacetamide) and 3,9-PC2AMtBu (2,2’-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,9-diyl)bis(N-tert-butyl)acetamide) which contain a pyclen platform functionalized with acetamide or tert-butylacetamide pendant arms at positions 3 and 9 of the macrocyclic unit. The corresponding Co(II) and Ni(II) complexes were prepared, isolated and characterised as potential paramagnetic chemical exchange saturation transfer (paraCEST) agents. The X-ray structures of the Ni(II) complexes reveal six-coordination of the ligands to the metal ion. The Co(II) complex with 3,9-PC2AMtBu shows a similar six-coordinate structure in the solid state, while the Co(II) complex with 3,9 PC2AMH contains a seven-coordinate metal ion, seventh coordination being completed by the presence of an inner-sphere water molecule. The structure of the Co(II) complexes was investigated using 1H NMR spectroscopy and computational methods. The complexes present a seven-coordinate structure in solution, as demonstrated by the analysis of the paramagnetic shifts using density functional theory. Ligand protonation constants and stability constants of the complexes with 3,9 PC2AMH were determined using potentiometric titrations (I=0,15 M NaCl). The Co(II) complex was found to be more stable than the Ni(II) analogue (log KCoL = 14.46(5) and log KNiL = 13.15(3)). However, the Ni(II) and Co(II) complexes display similar rate constants characterizing the proton-assisted dissociation mechanism. The presence of highly shifted 1H NMR signals due to the amide protons in slow exchange with bulk water results in sizeable CEST signals, which are observed at +67 and +15 ppm for the Co(II) complex with 3,9 PC2AMH and +42 and +7 ppm for the Ni(II) analogue at 25ºC .Agencia Estatal de Investigación | Ref. CTQ2016-76756-PXunta de Galicia | Ref. ED431B 2020/52Nemzeti Kutatási Fejlesztési és Innovációs Hivatal | Ref. K-120224Nemzeti Kutatási Fejlesztési és Innovációs Hivatal | Ref. K-134694Science and Technology Commission of Shanghai Municipality | Ref. 2019SHZDZX0

Mn2+ complexes containing sulfonamide groups with pH-responsive relaxivity

We present two ligands containing a N-ethyl-4-(trifluoromethyl)benzenesulfonamide group attached to either a 6,6'-(azanediylbis(methylene))dipicolinic acid unit (H3DPASAm) or a 2,2'-(1,4,7-triazonane-1,4-diyl)diacetic acid macrocyclic platform (H3NO2ASAm). These ligands were designed to provide pH-dependent relaxivity response upon complexation with Mn2+ in aqueous solution. The protonation constants of the ligands and the stability constants of the Mn2+ complexes were determined using potentiometric titrations complemented by spectrophotometric experiments. The deprotonation of the sulfonamide groups of the ligands are characterized by protonation constants of logKiH = 10.36 and 10.59 for DPASAm3 and HNO2ASAm2 , respectively. These values decrease dramatically to logKiH = 6.43 and 5.42 in the presence of Mn2+ due to the coordination of the negatively charged sulfonamide groups to the metal ion. The higher logKiH value in [Mn(DPASAm)] is related to the formation of a seven-coordinate complex, while the metal ion in [Mn(NO2ASAm)] is six-coordinated. The X ray crystal structure of Na[Mn(DPASAm)(H2O)]·2H2O confirms the formation of a seven-coordinate complex, where the coordination environment is fulfilled by the donor atoms of the two picolinate groups, the amine N at-om, the N atom of the sulfonamide group and a coordinated water molecule. The lower conditional stability of the [Mn(NO2ASAm)] complex and the lower protonation constant of the sulfonamide group results in complex dissociation at relatively high pH (< 7.0). However, protonation of the sulfonamide group in [Mn(DPASAm)] falls into the physiologically relevant pH window and causes a significant increase in relaxivity from r1p = 3.8 mM 1 s 1 at pH 9.0 to r1p = 8.9 mM 1 s 1 at pH 4.0 (10 MHz, 25 ºC).Agencia Estatal de Investigación | Ref. CTQ2016-76756-PXunta de Galicia | Ref. ED431B 2017/59Xunta de Galicia | Ref. ED431D 2017/01Xunta de Galicia | Ref. ED481A-2018/314Universitá degli Studi del Piemonte OrientaleMinisterio de Ciencia, Innovación y Universidades | Ref. BEAGAL18/0014

Lanthanide(III) complexes based on an 18-membered macrocycle containing acetamide pendants. Structural characterization and paraCEST properties

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGWe report a detailed investigation of the coordination properties of macrocyclic lanthanide complexes containing a 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane scaffold functionalized with four acetamide pendant arms. The X-ray structures of the complexes with the large Ln3+ ions (La and Sm) display 12- and 10-coordinated metal ions, where the coordination sphere is fulfilled by the six N atoms of the macrocycle, the four O atoms of the acetamide pendants, and a bidentate nitrate anion in the La3+ complex. The analogous Yb3+ complex presents, however, a 9-coordinated metal ion because one of the acetamide pendant arms remains uncoordinated. 1H NMR studies indicate that the 10-coordinated form is present in solution throughout the lanthanide series from La to Tb, while the smaller lanthanides form 9-coordinated species. 1H and 89Y NMR studies confirm the presence of this structural change because the two species are present in solution. Analysis of the 1H chemical shifts observed for the Tb3+ complex confirms its D2 symmetry in aqueous solution and evidences a highly rhombic magnetic susceptibility tensor. The acetamide resonances of the Pr3+ and Tb3+ complexes provided sizable paraCEST effects, as demonstrated by the corresponding Z-spectra recorded at different temperatures and studies on tube phantoms recorded at 22 °C.China Scholarship CouncilMinisterio de Ciencia e Innovación | Ref. CTQ2011-24487Agencia Estatal de Investigación | Ref. PID2019-104626GB-I0

Inert macrocyclic Eu 3+ complex with affirmative paraCEST features

We report on a macrocyclic platform based on an 18-membered macrocycle that forms kinetically highly inert paramagnetic complexes and possesses an excellent outlook for the development of bioresponsive paraCEST (paramagnetic chemical exchange saturation transfer) contrast agents. The investigated europium(III) chelate is non-hydrated and contains four amide groups, each possessing two paramagnetically shifted proton resonances distant from bulk water. The X-ray crystal structure and solution studies indicate that the metal ion is ten-coordinated, being directly bound to the six N atoms of the macrocycle and the four amide O atoms of the pendant arms. The complex presents an excellent inertness with respect to dissociation, being stable under a variety of harsh conditions, including highly acidic and basic media or elevated temperatures. The amide protons are in slow-to-intermediate exchange with bulk water, which gives rise to the generation of a strong CEST effect at low probe concentration and saturation powers (∼25% at 5 mM, B1 = 5 μT, 37 °C). We demonstrate the potential of this platform for mapping pH in its microenvironment and foresee potential for the development of diverse paraCEST probes and sensorsMinisterio de Economía y Competitividad | Ref. CTQ2016-76756-PXunta de Galicia | Ref. ED431B 2017/59Xunta de Galicia | Ref. ED431D 2017/01German Research Foundation | Ref. DFG, grant ZA 814/2-1European Union’s Horizon 2020 | Ref. Grant Agreement N. 66751

Associations between RNA-Binding Motif Protein 3, Fibroblast Growth Factor 21, and Clinical Outcome in Patients with Stroke

Background: RNA-binding motif protein 3 (RBM3) is a cold-induced marker of good functional outcome of ischemic stroke that is promising as a protective target. Fibroblast growth factor 21 (FGF21) is an obesity- and temperature-related hormone that upregulates the expression of RBM3, which is beneficial as a recombinant treatment and has been tested under different experimental pathological conditions, including stroke. However, the interaction between RBM3 and FGF21 has not yet been tested for clinical stroke conditions. Methods: In a sample of 66 stroke patients, we analyzed the associations between the FGF21 and RBM3 serum concentrations on admission and at 72 h, body weight, maximum temperature during the first 24 h, and the outcome of patients at 3 months. We also analyzed their association with biomarkers of obesity (adiponectin and leptin) and inflammation (interleukin-6 (IL-6) and interleukin (IL-10)). Results: Higher concentrations of FGF21 on admission and RBM3 at 72 h were associated with good outcomes. Serum FGF21 and RBM3 were directly related to body mass index and inversely related to the maximum temperature during the first 24 h. We found a positive association between the FGF21 concentrations in obese patients with leptin and a negative correlation with adiponectin in non-obese participants. Conclusions: This clinical study demonstrates the association between RBM3 and FGF21 levels and the outcome of stroke patients. Although further investigations are required, these data support the pharmacological induction of RBM3 as a promising protective therapy