Six-coordinate Iron(II) and Cobalt(II) paraSHIFT Agents for Measuring Temperature by Magnetic Resonance Spectroscopy

<u>Para</u>magnetic Fe­(II) and Co­(II) complexes are utilized as the first transition metal examples of ¹H NMR <u>shift</u> agents (paraSHIFT) for thermometry applications using <u>M</u>agnetic <u>R</u>esonance <u>S</u>pectroscopy (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 (<i>T</i>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 <i>T</i>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 <i>T</i>₁ values suggests that these complexes, in particular the TMPC-based complexes, show promise as paraSHIFT agents for thermometry

Six-coordinate Iron(II) and Cobalt(II) paraSHIFT Agents for Measuring Temperature by Magnetic Resonance Spectroscopy

<u>Para</u>magnetic Fe­(II) and Co­(II) complexes are utilized as the first transition metal examples of ¹H NMR <u>shift</u> agents (paraSHIFT) for thermometry applications using <u>M</u>agnetic <u>R</u>esonance <u>S</u>pectroscopy (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 (<i>T</i>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 <i>T</i>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 <i>T</i>₁ values suggests that these complexes, in particular the TMPC-based complexes, show promise as paraSHIFT agents for thermometry

Six-coordinate Iron(II) and Cobalt(II) paraSHIFT Agents for Measuring Temperature by Magnetic Resonance Spectroscopy

<u>Para</u>magnetic Fe­(II) and Co­(II) complexes are utilized as the first transition metal examples of ¹H NMR <u>shift</u> agents (paraSHIFT) for thermometry applications using <u>M</u>agnetic <u>R</u>esonance <u>S</u>pectroscopy (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 (<i>T</i>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 <i>T</i>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 <i>T</i>₁ values suggests that these complexes, in particular the TMPC-based complexes, show promise as paraSHIFT agents for thermometry

Gear Up for a pH Shift: A Responsive Iron(II) 2‑Amino-6-picolyl-Appended Macrocyclic paraCEST Agent That Protonates at a Pendent Group

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 <i>C</i>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

Gear Up for a pH Shift: A Responsive Iron(II) 2‑Amino-6-picolyl-Appended Macrocyclic paraCEST Agent That Protonates at a Pendent Group

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 <i>C</i>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

Low-Spin Fe(III) Macrocyclic Complexes of Imidazole-Appended 1,4,7-Triazacyclononane as Paramagnetic Probes

Two macrocyclic complexes of 1,4,7-triazacyclononane (TACN), one with <i>N</i>-methyl imidazole pendants, [Fe­(<b>Mim</b>)]³⁺, and one with unsubstituted NH imidazole pendants, [Fe­(<b>Tim</b>)]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(<b>Tim</b>)]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. <i>N</i>-Methylation of the imidazole pendants in [Fe­(<b>Mim</b>)]³⁺ produces a complex that dissociates more readily at high pH in comparison to [Fe­(<b>Tim</b>)]³⁺, which contains ionizable donor groups. Cyclic voltammetry studies show that the redox potential of [Fe­(<b>Mim</b>)]³⁺ is invariant with pH (<i>E</i>_1/2 = 328 ± 3 mV vs NHE) between pH 3.2 and 8.4, unlike the Fe­(III) complex of <b>Tim</b> 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 (μ_eff value = 2.7–3.2) for both complexes. Solid-state measurements show that the susceptibility is consistent with a <i>S</i> = 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(<b>Mim</b>)]­(OTf)₃ shows a six-coordinate all-nitrogen bound Fe­(III) in a distorted octahedral environment. Relativistic <i>ab initio</i> wave function and density functional theory (DFT) calculations on [Fe­(<b>Mim</b>)]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 <i>S</i> = 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