Dramatic enhancement in pH sensitivity and signal intensity through ligand modification of a dicobalt PARACEST probe

Article abstract of DOI:10.1039/C8CC09520E

The employment of an ancillary amine-substituted bisphosphonate ligand affords a dicobalt complex able to quantitate pH with a remarkably high sensitivity of 8.8(5) pH unit^?1 at 37 °C through a ratiometric paramagnetic chemical exchange saturation transfer (PARACEST) approach, where the different pH dependences of amine and amide CEST peak intensities are utilized.

Full text of DOI:10.1039/C8CC09520E

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Dramatic enhancement in pH sensitivity and signal
intensity through ligand modification of a dicobalt
PARACEST probe†
Cite this: Chem. Commun., 2019,
55, 794
Received 30th November 2018,
Accepted 14th December 2018
Agnes E. Thorarinsdottir
and T. David Harris
*
DOI: 10.1039/c8cc09520e
rsc.li/chemcomm
The employment of an ancillary amine-substituted bisphosphonate typically show a strong pH dependence,5f,g,6c,13 a dramatic change
ligand affords a dicobalt complex able to quantitate pH with a in CEST signal intensity with pH can be achieved. However, due
remarkably high sensitivity of 8.8(5) pH unitꢀ1 at 37 8C through a to the inherent concentration dependence of the intensity of
ratiometric paramagnetic chemical exchange saturation transfer CEST peaks, a ratiometric method is required to effectively
(PARACEST) approach, where the different pH dependences of exploit the CEST signal intensity for pH mapping in physiological
amine and amide CEST peak intensities are utilized.
environments, where the distribution of the probe is usually
unknown. Toward this end, a single PARACEST probe that
Bioresponsive molecular magnetic resonance imaging (MRI) features two types of exchangeable protons that display markedly
contrast agents are of tremendous interest for visualizing and different pH-dependent changes in CEST signal intensity offers
monitoring biological processes.1 MRI is ideally suited for an ideal platform, as the ratio of the two peak intensities should
molecular imaging in vivo owing to its high spatiotemporal image be highly sensitive to pH variations.
resolution and unlimited tissue penetration depth,2 but biorespon-
We recently employed this approach to demonstrate the
sive contrast agents are needed to improve specificity and add ability of dicobalt PARACEST probes to measure solution pH
valuable physiological information to the anatomical images.3 These in a physiologically relevant range with high sensitivities of
molecular probes undergo changes in MRI signals in response to 0.99(7)–2.04(5) pH unitꢀ1 5f,g
These probes feature a phenoxo-
.
variations in biomarkers such as temperature,1a,c,4 pH,1a,c,5 redox centered tetra(carboxamide) ligand and an ancillary bisphos-
status,1a,6 enzymes,1a,c,7 metal ions,1a,8 and metabolites,1a,c,9 and are phonate ligand bearing amide and hydroxyl protons, respectively,
therefore capable of reporting on their local physiological environ- with opposing pH-dependent CEST peak intensities (see Fig. 1, 1
ment. In particular, pH-responsive probes are attractive since acidic and 2-X). Notably, the chemical shifts and intensities of the CEST
extracellular pH is a prominent feature of various diseases and signals could be tuned by chemically modifying the pendent amides
disorders.10 As such, the ability to differentiate small changes in and para-substituents on the phenoxo-centered ligand.5g Building
pH through MRI is an important step toward improving the under- on these results, we sought to increase the pH sensitivity and signal
standing, early detection, and treatment of pathologies.
intensities of this family of ratiometric PARACEST probes by
In targeting pH-responsive MRI contrast agents, the employment modifying the ancillary bisphosphonate ligand. Herein, we report
of paramagnetic transition metal complexes that exploit the a new dicobalt complex that features an amine-substituted bisphos-
chemical exchange saturation transfer (CEST) mechanism is a phonate ligand and exhibits dramatically enhanced pH sensitivity
promising strategy owing to their high sensitivity to environmental by virtue of an intense and pH-insensitive CEST signal from the
changes and tunability through ligand design.11 Here, contrast is distant amine group.
generated through proton exchange between the paramagnetic
In an attempt to address the modest intensity and pH-dependent
molecule and bulk H2O upon frequency-specific irradiation.12 frequency of the etidronate hydroxyl CEST peak for our previously
The large chemical shifts of the exchangeable protons on these reported PARACEST probes,5f,g we targeted the amine-substituted
paramagnetic probes4b,5f,g,6c,d,13 improve sensitivity and specificity bisphosphonate ligand (L0)4ꢀ, with the expectation that the equiva-
by minimizing overlap with biological background signals.14 lent amine protons would give rise to a stronger CEST effect.
Moreover, since the exchange rates of these ligand protons Furthermore, the different pKa values of amine and amide protons
have been shown to result in distinct pH-dependent changes in
CEST peak intensity suitable for ratiometric pH sensing, albeit only
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston,
IL, 60208-3113, USA. E-mail: dharris@northwestern.edu
for probes that exhibit small chemical shifts and modest pH
sensitivity.15 As such, we envisioned that a dinucleating ligand
† Electronic supplementary information (ESI) available: Experimental details and
additional magnetic and spectroscopic data. See DOI: 10.1039/c8cc09520e
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Fig. 1 Structures of previously reported dicobalt PARACEST pH probes [LCo2(etidronate)]ꢀ (left) and [(XL0)Co2(etidronate)]ꢀ (center), as observed in 1 and
2-X (X = NO2, F, Me), respectively, and the new dicobalt complex LCo2(HL0) (right), as observed in 3, reported here. The exchangeable amide, hydroxyl,
and amine protons are highlighted in green, orange, and purple, respectively.
platform comprised of (L0)4ꢀ and a phenoxo-centered tetra(carbox- buffered to selected pH values. The spectrum at pH 7.02 exhibits
amide) ligand known for providing highly shifted and pH-sensitive sharp and paramagnetically shifted resonances with chemical
amide CEST peaks could afford dicobalt PARACEST probes better shifts from ꢀ103 to 182 ppm versus H2O (see Fig. S5, upper, ESI†),
suited for ratiometric pH quantitation.
consistent with the presence of high-spin CoII.11 Comparison to
Reaction of the nitro-substituted tetra(carboxamide) ligand the spectrum recorded in D2O (see Fig. S5, lower, ESI†) and the
HL with two equivalents of Co(NO3)2ꢁ6H2O in the presence of spectrum for 1 at pH 7.06 (see Fig. S6, ESI†) reveals that the
one equivalent of H4L0 in H2O at pH 7.5 afforded Na[LCo2L0]ꢁ resonances at 4, 6, 11, 13, 66, 68, 103, and 106 ppm correspond to
3.8NaNO3ꢁ5.9H2O (see Fig. 1, 3) as an orange solid (see Experi- four sets of two slightly inequivalent amide protons, whereas the
mental section, ESI†). Slow diffusion of MeCN vapor into a peaks at 48 and 101 ppm correspond to amine and hydroxyl
concentrated H2O solution of 3 gave light orange plate-shaped protons on (HL0)3ꢀ, respectively. Furthermore, the two methylene
crystals that were not of sufficient quality for single-crystal X-ray protons on (HL0)3ꢀ resonate at 69 and 74 ppm, in accord with the
diffraction analysis. However, the close similarity between the etidronate methyl peak at 66 ppm for 1. Together, these observa-
diffuse reflectance UV-visible spectra for 10 and 3 (see Fig. S2, tions indicate pseudo-C2 symmetry of LCo2(HL0) in 3, as observed
ESI†) suggests analogous solid-state structures.5f
for the anionic complexes in 1 and 2-X.5f,g Moreover, the close
To assess the electronic structure of 3 in aqueous solution, similarity between the 1H NMR profiles for 1 and 3 corroborates
UV-visible absorption spectra were collected for samples in our previous observations that the chemical shifts of resonances
50 mM HEPES buffers with 100 mM NaCl. For a solution at from Lꢀ are not significantly affected by modest modifications of
pH 6.98, the spectrum exhibits a single strong peak at 371 nm the bisphosphonate ligand.5f Importantly, the amine resonance
(e = 12 400 Mꢀ1 cmꢀ1) (see Fig. S3, ESI†), which is consistent for 3 is highly shifted and well separated from the amide peaks,
with the spectra for 1 and 2-NO25f,g and can be unambiguously suggesting the potential utility of these two functional groups for
assigned to a ligand-metal charge transfer (LMCT) transition pH sensing using ratiometric PARACEST. Finally, whereas no
from the bridging phenolate to CoII.16 Note that the position chemical shift changes are observed upon increasing the pH
and intensity of this band are essentially identical between pH 6.1 from 5.99 to 7.80, the exchangeable proton resonances broaden
and 8.0, indicating the presence of a single species in solution in significantly, indicating faster proton exchange (see Fig. S7, ESI†).
this pH range. Based on precedent in amine-bisphosphonate
To further investigate the possibility of employing 3 as a
molecular complexes,17 in conjunction with a notable increase in pH-responsive PARACEST probe, variable-pH CEST spectra were
solubility of 3 at more alkaline pH, we assign this species to the collected at 37 1C for 9 mM solutions of 3 in HEPES buffers. The
neutral dicobalt complex LCo2(HL0), where the amine of the bisphos- spectrum at pH 6.01 exhibits three peaks at 48, 67, and 100 ppm
phonate ligand is protonated.
with 36, 2.1, and 4.8% CEST intensity, respectively (see Fig. 2,
The oxidation state and spin state of Co in 3 was further probed upper). The CEST peaks at 48 and 67 ppm correspond to amine
by variable-pH magnetic susceptibility measurements for aqueous and two overlapping amide resonances, respectively, as evidenced
buffer solutions at 37 1C using the Evans method.18 The wMT data do by 1H NMR analysis. As the pH is raised to 7.58, the intensity of the
not significantly change in the pH range 6.1–8.0, affording an amine peak remains relatively constant, reaching a maximum value
average value of wMT = 5.96(6) cm3 K molꢀ1 (see Fig. S4 and of 42% at pH 7.01. However, further increasing the pH to 7.78 leads
Table S1, ESI†). These data are in good agreement with those to a significant peak broadening and concurrent intensity reduction
obtained for 1 and 2-X, indicative of pseudo-octahedral high-spin (see Fig. 2). In stark contrast, the CEST effect at 67 ppm increases
CoII centers (S = 3/2) with significant magnetic anisotropy.5f,g,11a,16b,19 nearly linearly in this pH range, affording a maximum value of 23%
To further probe the solution structure and properties of 3, at pH 7.78 (see Fig. 2). This increase in CEST peak intensity with
1H NMR spectra were collected at 37 1C for aqueous solutions pH is consistent with the base-catalyzed amide proton exchange
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decrease and a fit to the data provided a pH calibration curve with
the following equation (see Fig. 3):
CEST48ppm/CEST67ppm = ꢀ8.8 ꢂ pH + 67
(1)
Remarkably, the pH sensitivity of 8.8(5) for 3, as estimated by
the absolute value of the slope of the linear calibration curve, is over
4-fold higher than for other dicobalt complexes in this family of
PARACEST pH probes.5f,g In fact, to our knowledge, 3 exhibits the
highest pH sensitivity in the physiological range yet reported for a
ratiometric MR-based paramagnetic probe at 37 1C.21 The dramatic
increase in pH sensitivity for 3 stems from the linear relationship
between CEST48ppm/CEST67ppm and pH, rather than the logarithm of
the intensity ratios, as observed for all previously reported dicobalt
analogues.5f,g Importantly, the pH calibration curve for 3 is not
significantly affected by the concentration of the complex, as the
slopes obtained for 5 and 9 mM samples of 3 fall within error of one
another (see Fig. S11–S16, ESI†). This observation illustrates that the
ratiometric method using 3 provides a concentration-independent
measure of pH in the range 6.20–7.41, which is in line with previous
findings for 1 and 2-X.5f,g Taken together, these results show that a
substantial sensitivity improvement in ratiometric pH quantitation
is achieved by using an amine-functionalized dinucleating ligand
platform. Furthermore, the amine group from (HL0)3ꢀ affords a
CEST peak with much higher intensity than does the etidronate
hydroxyl group in 1 and 2-X.5f,g
The observation of no shifts in 1H NMR frequencies between
pH 6.0 and 7.8 for 3 contrasts with that of 1 and 2-X,5f,g suggesting
Fig. 2 Upper: Variable-pH CEST spectra collected at 11.7 T and 37 1C
using a 2 s presaturation pulse and B1 = 22 mT for 9 mM aqueous solutions
of 3 with 50 mM HEPES and 100 mM NaCl buffered to pH 6.01–7.78 (see that the pKa corresponding to protonation of one of the cobalt-
legend). Inset: Expanded view of the CEST peaks of interest. Lower: Plot of
CEST intensities from presaturation at 48 ppm (purple) and 67 ppm (green)
versus pH.
0
coordinated OL atoms (see Fig. S17, ESI†) is significantly lower for 3
than for 1 and 2-X.5f,g Indeed, sigmoidal fits (see Experimental
section, ESI†) to the chemical shift versus pH data for the two
methylene resonances from the bisphosphonate ligand between
pH 1.50 and 7.80 gave values of pKa = 3.57(8) and 3.96(4) for 3 (see
Fig. S18, ESI†). The slight discrepancy between the pKa values
estimated from the two protons likely arises from their different
distances from the OL atoms. Most importantly, both values are
substantially lower than those of 5.01(3) and 4.76(7) reported for 1
and 2-NO2, respectively,5f,g indicating that pH-induced shifts in
observed for 1 and 2-X.5f,g Indeed, exchange rate analysis using
the Omega plot method20 reveals that the rate constant (kex) for
the amide protons at 67 ppm for 3 increases from 2.9(4) ꢂ 102 to
6.1(1) ꢂ 102 sꢀ1 between pH 6.53 and 7.78 (see Fig. S8 and S10,
ESI†). These values agree well with those previously reported for
dicobalt complexes of Lꢀ.5f To compare, kex for the amine
protons in 3 exhibits a relatively small pH dependence below
pH 7.0 but then undergoes a dramatic increase when the pH is
raised further, reaching a maximum of kex = 1.5(1) ꢂ 103 sꢀ1 at
pH 7.78 (see Fig. S9 and S10, ESI†). These observations are
consistent with NMR line width and CEST intensity analyses,
indicating that kex = 800–900 sꢀ1 provides optimal amine CEST
effect for the dinuclear system. Finally, note that the CEST peak
at 100–103 ppm stems from overlapping amide and hydroxyl
resonances, as observed for 1.5f Despite the high chemical shift,
the broadness of this peak and pH-dependent frequency render
it unsuitable for use in ratiometric pH quantitation.
0
The markedly different pH dependences of the amine and
amide CEST intensities at 48 and 67 ppm, respectively, prompted us
to assess the utility of 3 in the ratiometric quantitation of pH.
Indeed, the ratio of CEST intensities at 48 and 67 ppm (CEST48ppm
CEST67ppm) exhibits a pronounced pH dependence. Upon increasing
the pH from 6.20 to 7.41, CEST48ppm/CEST67ppm shows a linear
/
Fig. 3 Plot of the ratios of CEST intensities from presaturation at 48 and
67 ppm for 9 mM aqueous buffer solutions of 3 versus pH. Circles denote
experimental data and the line corresponds to a linear fit to the data.
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