Comparison of divalent transition metal ion paraCEST MRI contrast agents

Dorazio, Sarina J.; Olatunde, Abiola O.; Tsitovich, Pavel B.; Morrow, Janet R.

doi:10.1007/s00775-013-1059-4

Cited by 71 publications

(127 citation statements)

References 90 publications

(188 reference statements)

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“…Most of these paraCEST agents incorporate lanthanide ions that are potentially toxic, limiting intravenous administration to concentrations below their CEST detection limit within in vivo tissues . Some paraCEST agents incorporate nontoxic metals, but their oxidation state for CEST MRI are relatively unstable, which may compromise their practical utility . Yet many of the 42 paraCEST agents that have been reported have shown good utility for molecular imaging studies of small animal models …”

Section: Exogenous Cest Agentsmentioning

confidence: 99%

Clinical applications of chemical exchange saturation transfer (CEST) MRI

Jones

Pollard

Pagel

2017

Magnetic Resonance Imaging

222

246

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Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) has been developed and employed in multiple clinical imaging research centers worldwide. Selective radiofrequency (RF) saturation pulses with standard 2D and 3D MRI acquisition schemes are now routinely performed, and CEST MRI can produce semiquantitative results using magnetization transfer ratio asymmetry (MTRasym) analysis while accounting for B0 inhomogeneity. Faster clinical CEST MRI acquisition methods and more quantitative acquisition and analysis routines are under development. Endogenous biomolecules with amide, amine, and hydroxyl groups have been detected during clinical CEST MRI studies, and exogenous CEST agents have also been administered to patients. These CEST MRI tools show promise for contributing to assessments of cerebral ischemia, neurological disorders, lymphedema, osteoarthritis, muscle physiology, and solid tumors. This review summarizes the salient features of clinical CEST MRI protocols and critically evaluates the utility of CEST MRI for these clinical imaging applications. Level of Evidence: 5 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:11–27.

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Section: Exogenous Cest Agentsmentioning

confidence: 99%

Clinical applications of chemical exchange saturation transfer (CEST) MRI

Jones

Pollard

Pagel

2017

Magnetic Resonance Imaging

222

246

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“…48,49 Our previous work has shown that Fe(II), Co(II) and Ni(II) complexes produce highly shifted and often relatively narrow proton resonances to give complexes that function as paraCEST agents. 26,50–52 For these transition metal ions, contact (through-bond) contributions to the hyperfine shifts are expected to be substantial. 53 Thus hyperfine shifts can be quite large even for paramagnetic metal ions such as Co(II) and Fe(II) that have relatively small magnetic moments in comparison to lanthanides that demonstrate highly shifted proton resonances such as Dy(III) and Tm(III).…”

Section: Introductionmentioning

confidence: 99%

“…57–60 For example, as reported by our group, all of the Fe(II) and Co(II) complexes of TACN and CYCLEN appended with amide groups give broad proton resonances due to their structural fluxionality. 52 In contrast, heterocyclic pendents attached to a TACN framework generally give more rigid Fe(II) and Co(II) complexes. 26,50,51 Additionally, while CYCLEN-based Ln(III) complexes often produce several structural isomers detectable on the 1 H NMR time-scale, 57,59 it is preferable to prepare new complexes that exist in a single diastereomeric form in aqueous solutions.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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 (T1) 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 three-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 T1 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 T1 values suggests that these complexes, in particular the TMPC-based complexes, show promise as paraSHIFT agents for thermometry.

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“…28 In contrast, the rate constants for exchange of NH protons of amide pendents are low, ranging from 300 to 800 s −1 at neutral pH. 20 ParaCEST agents with amide pendents generally undergo base-catalyzed proton exchange with CEST peak intensity and corresponding exchange rate constants increasing with pH.…”

Section: Discussionmentioning

confidence: 99%

“…19–20 In particular, CEST MRI is of special interest due to the intrinsic responsiveness of the exchangeable protons of the contrast agent to the environment. 21 These exchangeable protons are key to producing contrast through decreasing the water proton resonance intensity.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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 C2-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 pH 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 towards the development of probes for concentration independent imaging of pH.

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Comparison of divalent transition metal ion paraCEST MRI contrast agents

Cited by 71 publications

References 90 publications

Clinical applications of chemical exchange saturation transfer (CEST) MRI

Clinical applications of chemical exchange saturation transfer (CEST) MRI

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

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

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