Paramagnetic Fe(II) and Co(II) complexes are utilized as the first transition metal examples of 1H NMR shift agents (paraSHIFT) for thermometry applications using Magnetic Resonance Spectroscopy ...(MRS). The coordinating ligands consist of TACN (1,4,7-triazacyclononane) and CYCLEN (1,4,7,10-tetraazacyclododecane) azamacrocycles appended with 6-methyl-2-picolyl groups, denoted as MPT and TMPC, respectively. 1H NMR spectra of the MPT- and TMPC-based Fe(II) and Co(II) complexes demonstrate narrow and highly shifted resonances that are dispersed as broadly as 440 ppm. The six-coordinate complex cations, M(MPT)2+ and M(TMPC)2+, vary from distorted octahedral to distorted trigonal prismatic geometries, respectively, and also demonstrate that 6-methyl-2-picolyl pendents control the rigidity of these complexes. Analyses of the 1H NMR chemical shifts, integrated intensities, line widths, the distances obtained from X-ray diffraction measurements, and longitudinal relaxation time (T 1) values allow for the partial assignment of proton resonances of the M(MPT)2+ complexes. Nine and six equivalent methyl protons of M(MPT)2+ and M(TMPC)2+, respectively, produce 3-fold higher 1H NMR intensities compared to other paramagnetically shifted proton resonances. Among all four complexes, the methyl proton resonances of Fe(TMPC)2+ and Co(TMPC)2+ at −49.3 ppm and −113.7 ppm (37 °C) demonstrate the greatest temperature dependent coefficients (CT) of 0.23 ppm/°C and 0.52 ppm/°C, respectively. The methyl groups of these two complexes both produce normalized values of |CT|/fwhm = 0.30 °C–1, where fwhm is full width at half-maximum (Hz) of proton resonances. The T 1 values of the highly shifted methyl protons are in the range of 0.37–2.4 ms, allowing rapid acquisition of spectroscopic data. These complexes are kinetically inert over a wide range of pH values (5.6–8.6), as well as in the presence of serum albumin and biologically relevant cations and anions. The combination of large hyperfine shifts, large temperature sensitivity, increased signal-to-noise ratio, and short T 1 values suggests that these complexes, in particular the TMPC-based complexes, show promise as paraSHIFT agents for thermometry.
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Trigger ready: A redox‐activated MRI contrast agent can cycle between paramagnetic CoII (MRI‐active) and diamagnetic CoIII (MRI‐silent). The paramagnetic CoII form produces a highly shifted CEST ...signal at 135 ppm (37 °C). The redox state of the Co complex is altered by O2 partial pressure and reductant concentration (thiols) on a time scale relevant to imaging. MT=magnetization transfer.
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Two macrocyclic complexes of 1,4,7-triazacyclononane (TACN), one with N-methyl imidazole pendants, Fe(Mim)3+, and one with unsubstituted NH imidazole pendants, Fe(Tim)3+, were prepared with a view ...toward biomedical imaging applications. These low-spin Fe3+ complexes produce moderately paramagnetically shifted and relatively sharp 1H NMR resonances for paraSHIFT and paraCEST applications. The Fe(Tim)3+ complex undergoes pH-dependent changes in NMR spectra in solution that are consistent with the consecutive deprotonation of all three imidazole pendant groups at high pH values. N-Methylation of the imidazole pendants in Fe(Mim)3+ produces a complex that dissociates more readily at high pH in comparison to Fe(Tim)3+, which contains ionizable donor groups. Cyclic voltammetry studies show that the redox potential of Fe(Mim)3+ is invariant with pH (E 1/2 = 328 ± 3 mV vs NHE) between pH 3.2 and 8.4, unlike the Fe(III) complex of Tim which shows a 590 mV change in redox potential over the pH range of 3.3–12.8. Magnetic susceptibility studies in solution give magnetic moments of 0.91–1.3 cm3 K mol–1 (μeff value = 2.7–3.2) for both complexes. Solid-state measurements show that the susceptibility is consistent with a S = 1/2 state over the temperature range of 0 to 300 K, with no crossover to a high-spin state under these conditions. The crystal structure of Fe(Mim)(OTf)3 shows a six-coordinate all-nitrogen bound Fe(III) in a distorted octahedral environment. Relativistic ab initio wave function and density functional theory (DFT) calculations on Fe(Mim)3+, some with spin orbit coupling, were used to predict the ground spin state. Relative energies of the doublet, quartet, and sextet spin states were consistent with the doublet S = 1/2 state being the lowest in energy and suggested that excited states with higher spin multiplicities are not thermally accessible. Calculations were consistent with the magnetic susceptibility determined in the solid state.
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Two high-spin Fe(II) and Co(II) complexes of 1,4,7,10-tetraazacyclododecane (CYCLEN) appended with four 2-amino-6-picolyl groups, denoted as Fe(TAPC)2+ and Co(TAPC)2+, are reported. These ...complexes demonstrate C 2-symmetrical geometry from coordination of two pendents, and they are present in a single diastereomeric form in aqueous solution as shown by 1H NMR spectroscopy and by a single-crystal X-ray structure for the Co(II) complex. A highly shifted but low-intensity CEST (chemical exchange saturation transfer) signal from NH groups is observed at −118 ppm for Co(TAPC)2+ at pH 6.0 and 37 °C. A higher intensity CEST peak is observed for Fe(TAPC)2+, which demonstrates a pH-dependent frequency shift from −72 to −79 ppm at pH 7.7 to 4.8, respectively, at 37 °C. This shift in the CEST peak correlates with the protonation of the unbound 2-amino-6-picolyl pendents, as suggested by UV–vis and 1H NMR spectroscopy studies at different pH values. Phantom imaging demonstrates the challenges and feasibility of using the Fe(TAPC)2+ agent on a low-field MRI scanner. The Fe(TAPC)2+ complex is the first transition-metal-based paraCEST agent that produces a pH-induced CEST frequency change toward the development of probes for concentration-independent imaging of pH.
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The reduction/oxidation (redox) potential of tissue is tightly regulated in order to maintain normal physiological processes, but is disrupted in disease states. Thus, the development of new tools to ...map tissue redox potential may be clinically important for the diagnosis of diseases that lead to redox imbalances. One promising area of chemical research is the development of redox-activated probes for mapping tissue through magnetic resonance imaging (MRI). In this review, we summarize several strategies for the design of redox-responsive MRI contrast agents. Our emphasis is on both lanthanide(III) and transition metal(II/III) ion complexes that provide contrast either as T1 relaxivity MRI contrast agents or as paramagnetic chemical exchange saturation transfer (PARACEST) contrast agents. These agents are redox-triggered by a variety of chemical reactions or switches including redox-activated thiol groups, and heterocyclic groups that interact with the metal ion or influence properties of other ancillary ligands. Metal ion centered redox is an approach which is ripe for development by coordination chemists. Redox-triggered metal ion approaches have great potential for creating large differences in magnetic properties that lead to changes in contrast. An attractive feature of these agents is the ease of fine-tuning the metal ion redox potential over a biologically relevant range.
A promising area of chemical research is the development of redox-activated probes for mapping tissue through magnetic resonance imaging (MRI). This focused review summarizes several strategies for the design of redox-responsive MRI contrast agents based on both lanthanide and transition metal ion complexes. Display omitted
•Redox-responsive MRI probes may enable mapping of biological redox potential.•Redox-sensitive ligands produce responsive GdIII MRI contrast agents.•Redox responsive Ln(III) PARACEST MRI contrast agents contain redox-activated ligands.•Metal ion complexes with variable oxidation states such as MnII/MnIII are highly tunable probes.•CoII/CoIII PARACEST agents switch from paramagnetic (MRI active) to diamagnetic (MRI silent).
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Fe(II) macrocyclic complexes are under development as MRI contrast agents for paramagnetic chemical exchange saturation transfer (paraCEST) and chemical shift imaging (paraCSI). Fe(II) complexes of ...triazamacrocycles or tetraazamacrocycles show paraCEST spectra with either amide, aminopyridine or benzimidazole groups. The dynamic nature of the complexes impacts their use as paraCSI agents. Display omitted
► Fe(II) macrocyclic complexes are under development as contrast agents for paraCEST and chemical shift magnetic resonance imaging. ► Stabilization of high spin Fe(II) complexes with hexadentate or octadentate macrocyclic ligands. ► Fe(II) complexes containing heterocycles or amide donor groups have exchangeable protons that give paraCEST spectra. ► Non-bulky pendent groups give Fe(II) complexes that are fluxional on the NMR time scale.
Fe(II) macrocyclic complexes are a relatively new addition to the class of MRI contrast agents that function through paraCEST (paramagnetic chemical exchange saturation transfer) or paraCSI (paramagnetic complex chemical shift imaging). Both methods require relatively narrow and highly shifted ligand proton resonances. For paraCEST, the protons are exchangeable with water (NH or OH); for paraCSI the protons are non-exchangeable and are on carbons (CH). We report on several macrocyclic ligands for Fe(II) including those based on CYCLEN (1,4,7,10-tetraazacyclododecane) and TACN (1,4,7-triazacyclononane) with attached pendent arms containing either benzimidazole, pyridine or amide donor groups. Paramagnetic proton NMR spectra and paraCEST spectra are reported for these complexes. Challenges include fluxionality of the macrocyclic complexes in solution which broadens the macrocycle proton resonances, especially for amide pendent groups. Despite this dynamic process, the exchangeable NH proton resonances of the amide pendent groups remain relatively sharp. These amide complexes are thus suitable for paraCEST but not paraCSI. The dynamic process is arrested in complexes containing pendent pyridine groups that lock the TACN macrocyclic Fe(II) complex into a single diastereomeric form over the temperature range of 15–45°C to produce an Fe(II) complex that is promising for paraCSI.
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7.
Iron(II) PARACEST MRI Contrast Agents Dorazio, Sarina J; Tsitovich, Pavel B; Siters, Kevin E ...
Journal of the American Chemical Society,
09/2011, Volume:
133, Issue:
36
Journal Article
Peer reviewed
Open access
The first examples of Fe(II) PARACEST magnetic resonance contrast agents are reported (PARACEST = paramagnetic chemical exchange saturation transfer). The iron(II) complexes contain a macrocyclic ...ligand, either 1,4,7-tris(carbamoylmethyl)-1,4,7-triazacyclononane (L1) or 1,4,7-tris(5-amino-6-methyl-2-pyridyl)methyl-1,4,7-triazacyclononane (L2). The macrocycles bind Fe(II) in aqueous solution with formation constants of log K = 13.5 and 19.2, respectively, and maintain the Fe(II) state in the presence of air. These complexes each contain six exchangeable protons for CEST which are amide protons in Fe(L1)2+ or amino protons in Fe(L2)2+. The CEST peak for the Fe(L1)2+ amide protons is at 69 ppm downfield of the bulk water resonance whereas the CEST peak for the Fe(L2)2+ amine protons is at 6 ppm downfield of bulk water. CEST imaging using a MRI scanner shows that the CEST effect can be observed in solutions containing low millimolar concentrations of complex at neutral pH, 100 mM NaCl, 20 mM buffer at 25 °C or 37 °C.
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Transition-metal-ion-based paramagnetic chemical exchange saturation transfer (paraCEST) agents are a promising new class of compounds for magnetic resonance imaging (MRI) contrast. Members in this ...class of compounds include paramagnetic complexes of Fe
II
, Co
II
, and Ni
II
. The development of the coordination chemistry for these paraCEST agents is presented with an emphasis on the choice of the azamacrocycle backbone and pendent groups with the goals of controlling the oxidation state, spin state, and stability of the complexes. Chemical exchange saturation transfer spectra and images are compared for different macrocyclic complexes containing amide or heterocyclic pendent groups. The potential of paraCEST agents that function as pH- and redox-activated MRI probes is discussed.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Several complexes of Co(ii) or Fe(ii) with 1,4,7,10-tetraazacyclododecane (CYCLEN) appended with 1,7-(6-methyl)2-picolyl groups are studied as
H NMR paraSHIFT agents (paramagnetic shift agents) for ...the registration of temperature. Two of the complexes, Co(BMPC)
and Fe(BMPC)
, contain methyl groups only on the methyl picolyl pendents. Two other complexes, Co(2MPC)
and Fe(2MPC)
, contain picolyl groups and also methyl groups on the macrocyclic amines. All macrocyclic complexes are in high spin form as shown by solution magnetic moments in the range of 5.0-5.9μ
and 5.3-5.8μ
for Co(ii) and Fe(ii) complexes, respectively. The
H NMR spectra of both of the Fe(ii) complexes and one of the Co(ii) complexes are consistent with a predominant diastereomeric form in deuterium oxide solutions. The highly shifted methyl proton resonances for Co(2MPC)
appear at 164 and -113 ppm for macrocycle and pendent picolyl methyls and show temperature coefficients of -0.58 ppm °C
and 0.49 ppm °C
, respectively. Fe(ii) complexes have less shifted methyl proton resonances and smaller temperature coefficients. The
H resonances of Fe(2MPC)
appear at 105 ppm and -46 ppm with corresponding temperature coefficients (CT) of -0.29 ppm °C
and 0.22 ppm °C
, respectively. The relatively narrow linewidths of Fe(2MPC)
, however, produce superior CT/FWHM values of 0.44 and 0.31 °C
for the N-methyl and picolyl proton resonances where FWHM is the full width at half maximum of the
H resonance. The crystal structure of Co(BMPC)Cl
shows a six-coordinate Co(ii) bound to the macrocyclic amines and two pendent picolyl groups. The distorted trigonal prismatic geometry of the complex resembles that of an analogous complex containing four 6-methyl-2-picolyl groups, in which only two picolyl pendents are coordinated.
A reversible Fe
/Fe
redox couple of an azamacrocyclic complex is evaluated as an electrolyte with a pH-tunable potential range for aqueous redox-flow batteries (RFBs). The Fe
complex is formed by ...1,4,7-triazacyclononane (TACN) appended with three 2-methyl-imidazole donors, denoted as Fe(Tim). This complex exhibits pH-sensitive redox couples that span E
(Fe
/Fe
)=317 to -270 mV vs. NHE at pH 3.3 and pH 12.8, respectively. The 590 mV shift in potential and kinetic inertness are driven by ionization of the imidazoles at various pH values. The Fe
/Fe
redox is proton-coupled at alkaline conditions, and bulk electrolysis is non-destructive. The electrolyte demonstrates high charge/discharge capacities at both acidic and alkaline conditions throughout 100 cycles. Given its tunable redox, fast electrochemical kinetics, exceptional stability/cyclability, this complex is promising for the design of aqueous RFB catholytes and anolytes that utilize the earth-abundant element iron.
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