Reinforced Ni(II)-cyclam derivatives as dual 1H/19F MRI probes

Article abstract of DOI:10.1039/c9cc01204d

Reinforced cross-bridged Ni²⁺-cyclam complexes were functionalised with pendant arms containing both amide protons and CF₃ groups that lead to a dual ¹H/¹⁹F response. The resulting complexes possess very high in

Full text of DOI:10.1039/c9cc01204d

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Paradela, T. Savi, I. Brandariz, P. Pérez-Lourido, G. Angelovski, D. Esteban and C. Platas-Iglesias, Chem.
Commun., 2019, DOI: 10.1039/C9CC01204D.
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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
first methanofullerene derivatives of Sc
3
N@C2n (2n
=
68 and 80). Synthesis of the
3
N@D5h-C80
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1
19
Reinforced Ni(II)-cyclam derivatives as dual H/ F
MRI Probes
a
b
a
c
b
Rosa Pujales-Paradela, Tanja Savić, Isabel Brandariz, Paulo Pérez-Lourido, Goran Angelovski,
Received 00th January 20xx,
Accepted 00th January 20xx
,a
,a
David Esteban-Gómez,* and Carlos Platas-Iglesias*
DOI: 10.1039/x0xx00000x
www.rsc.org/
2
+
were transfer. Paramagnetic ions such as the Ln3+ ions increase the
Reinforced
cross-bridged
Ni -cyclam
complexes
functionalised with pendant arms containing both amide protons chemical shift difference between the two pools of protons;
1
19
and CF
3
groups that lead to a dual H/ F response. The resulting consequently, the slow-to-intermediate exchange condition
6
complexes possess very high inertness favourable for MRI can be achieved with faster exchange rates. Furthermore,
applications. The paramagnetism of the Ni ion shifts the amide different CEST agents based on paramagnetic transition metal
resonance 56 ppm away from bulk water favouring the chemical ions have been also proposed (Fe , Co and Ni ). CEST
exchange saturation transfer (CEST) effect and shortening agents can be activated at will by applying a radiofrequency
acquisition times in the F magnetic resonance imaging (MRI) pulse, which opens the possibility of detecting different agents
2
+
2
+
2+
2+ 7
1
9
1
9
experiments, thus enhancing signal-to-noise ratios compared to simultaneously. 3) Using F-based probes, which represent
the fluorinated diamagnetic reference.
1
19
the best alternative to H given the high sensitivity of the
F
1
19
nucleus (83% with respect to H). F-based probes have the
advantage of the negligible fluoride concentration in vivo,
which eliminates any background signal. However,
presents rather long relaxation times (0.6 – 1.5 s), so that
paramagnetic metal ions are used to accelerate relaxation
times and thus acquisition times. This has been achieved both
Magnetic resonance imaging (MRI) contrast agents (CAs) are
generally paramagnetic metal complexes of Gd able to
reduce the longitudinal relaxation time (T
vicinity. These classical CAs are commonly used in clinical
practice, although recently there have been some concerns
about their toxicity. This prompted the European Medicines
Agency to restrict in 2017 the use of some non-macrocyclic
Gd contrast agents and suspend the authorizations for
others.3 Nevertheless, the use of macrocyclic Gd -based
contrast agents is thought to be safe and will likely continue in
the near future.
The safety aspects and some limitations of the Gd -based
probes triggered the development of different alternatives,
including: 1) Developing T shortening agents based on other
1
paramagnetic metal ions such as Mn ; 2) The use of agents
that provide contrast following the chemical exchange
saturation transfer (CEST) mechanism. CEST agents contain a
pool of protons in slow-to-intermediate exchange with bulk
water, so that applying a radiofrequency pulse to this proton
nuclei results in a decrease of bulk water signal by saturation
3
+
8
19
F
1
) of protons in their
8
1
2
9
10
with transition metal ions or lanthanides.
The combination of CEST H and 19F response into a single
1
3
+
CA may result in probes that combine the advantages of the
two techniques: The generation of on/off response at will by
CEST agents and the easier quantification of the MRI signal for
,4
3+
19
1
19
3+
F probes. Some examples of dual H/ F agents based on Ln
3
+
11
complexes were reported recently in the literature. Given the
3+
potential toxicity of probes based on Ln ions, we sought to
develop transition metal complexes showing this dual output.
We report here the first generation of these transition metal
2
+ 5
2+
CA candidates based on Ni . Stable complexation of this metal
ion was achieved with the use of reinforced (cross-bridge)
cyclam derivatives, functionalized with a carboxylate pendant
arm to ensure a good water solubility, and including a second
pendant arm containing an exchangeable amide proton for
1
9
CEST response and F nuclei (Fig. 1).
The synthesis of the ligands was achieved by sequential
alkylation of the commercially available cross-bridged
precursor with tert-butyl bromoacetate and the
chloroacetamide precursors (see ESI†). Hydrolysis of the tert-
a. Centro de Investigacións Científicas Avanzadas (CICA) and Departamento de
Química, Facultade de Ciencias, Universidade da Coruña, 15071 A Coruña, Galicia,
Spain. E-mail: carlos.platas.iglesias@udc.es
b.
MR Neuroimaging Agents, Max Planck Institute for Biological Cybernetics,
Tuebingen, Germany
Departamento de Química Inorgánica, Facultad de Ciencias, Universidade de Vigo,
As Lagoas, Marcosende, 36310 Pontevedra, Spain
1
2
c.
butyl groups with formic acid afforded the HL and HL ligands
with fair overall yields (17 and 21%, respectively). The
†Electronic Supplementary Information (ESI) available: Synthetic procedures and
2
+
preparation of the Ni complexes was achieved from the
experimental details. CCDCs 1891730 and 1891731. See DOI: 10.1039/x0xx00000x
1
+
nitrate and trifluoromethanesulfonate salts for [NiL ] and
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2
+
2 +
1 +
[
NiL ] , respectively, and required harsh conditions due to slow 2.110 Å for [NiL ] and [NiL ] , respectively). The macrocyclic
View Article Online
DOI: 10.1039/C9CC01204D
complexation kinetics, using n-butanol as a solvent and high unit adopts a cis-V conformation, with the bicyclo[6.6.2] ligand
temperature.12
units adopting [2323] conformations, as usually observed for
complexes of cross-bridged cyclam derivatives with small
1
4
metal ions.
R2
N
N
N
N
COOH
R1
R2
O
N
H
1
HL : R = H; R = CF
3
1
2
2
HL : R = CF ; R = H
1
3
2
Fig. 1. Chemical structures of the ligands reported in this work.
Fig. 3. UV-vis spectra of a 5.210-5 M fresh aqueous solution of [NiL ] and
2 +
that of the same solution registered 24 h later (25 ºC, 4M HCl). Insert:
2
+
Experimental ESI-MS spectra of the [NiL ] complex recorded in strong acidic
conditions after 5 days.
1
+
The inertness of the [NiL ] complex was assessed by using
spectrophotometric measurements. The absorption spectrum
of a 4 M HCl solution of the complex presents a maximum at
2
48 nm due to the phenylamide chromophore. The absorption
spectrum recorded after 24 h is identical to that recorded
immediately after dissolving the complex. Furthermore, the
mass spectrum of the solution obtained with electrospray
1
+
ionisation presents the peak of the [NiL ] entity at m/z =
5
4
42.19, while the peak of the protonated ligand at m/z =
86.26 was not observed (Fig. 3). These results confirm that
the complex is inert under these harsh conditions. For
-
instance, the [Gd(DOTA)] complex, which is used as a contrast
agent in clinical practice as DOTAREM®, undergoes dissociation
1
5
2
+
1
+
under these conditions with a half-live of 144 minutes.
Fig. 2. X-ray crystal structure of [NiL ] complex. Bond distances (Å): [NiL ]
Ni-O1 2.075(2); Ni-O3 2.026(1); Ni-N1 2.084(2); Ni-N2 2.071(2); Ni-N3
2
2
2
+
The two Ni complexes provide moderate CEST effects.
The measurements were carried out using 15 mM H O
solutions of the complexes containing 20% acetonitrile due to
2
+
.097(2); Ni-N4 2.070(2). [NiL ] : Ni-O1 2.0579(18); Ni-O3 2.1103(18); Ni-N1
.083(2); Ni-N2 2.082(2); Ni-N3 2.096(2); Ni-N4 2.068(2).
2
their low solubility in pure water (Fig. 4). The CEST spectra
o
present prominent CEST peaks at 56 ppm and 25 C in both
The structure of both complexes were determined using
1
+
2 + complexes due to the amide proton of the ligands, while the
X-ray diffraction measurements (Fig. 2). The [NiL ] and [NiL ]
complexes were crystallised as the chloride and
trifluoromethanesulfonate salts, respectively. The metal ion is
directly coordinated to the four N atoms of the macrocyclic
unit, with Ni-N distances in the range 2.07-2.10 Å. These values
fall in the low part of the range observed for the few cross-
shift reduces to ~52 ppm when the spectra were recorded at
7 C. This chemical shift is somewhat smaller than those
o
3
2
+
observed for Ni
acetamide
complexes with ligands containing
7
c,16
17
(typically 70 ppm) or picolinamide groups
(
85 ppm). The CEST spectra obtained with different
saturation powers were quantitatively analysed using the
standard Bloch-McConnell equations and 2 exchanging pools
paramagnetically shifted pool and bulk water), providing
exchange rates of amide protons of kex = 10.9 + 1.1 and 7.1 +
2
+
bridged Ni complexes reported in the literature (2.09-2.20
1
3
Å). The oxygen atoms of the pendant arms complete the
distorted octahedral coordination around the metal ion in
both cases. The Ni-O distance involving the carboxylate oxygen
1
8
(
1
+
2 +
1
+
2 +
1.7 kHz for [NiL ] and [NiL ] , respectively. The exchange of
atom (2.026 Å for [NiL ] and 2.058 Å for [NiL ] ) is slightly
shorter than that to the amide oxygen atom (2.075 Å and
amide protons generally follows
a
base-catalysed
1
7
1 +
mechanism. Thus, the higher rate determined for [NiL ] is
2
| Chem. Commun., 2016, 00, 1-3
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likely related to the more acidic character of the amide proton relaxation data and those estimated from the X-ray structures
View Article Online
DOI: 10.1039/C9CC01204D
due to the combined electron withdrawing effect of two CF
3
are in good mutual agreement.
substituents. However, given the fast exchange rates of both
complexes already at 25 C and the low solubility of the
complexes in water, further structural adjustments would be
necessary to optimise their properties for potential use as
o
Table 1. 19F longitudinal (R ) and transverse (R ) relaxation rates obtained
1
2
1
+
2 +
from 15 mM aqueous solutions of [NiL ] and [NiL ] containing 20%
acetonitrile and signal-to-noise rations (SNR) obtained with phantom MRI
a
studies (25 ⁰C, 7.05 T).
CEST MRI contrast agents (i. e. by incorporating the CF
3
groups
-
1
-1
2
SNRb
on the carbon atoms of the macrocycle at the -N position or
Complex
R (s )
R (s )
R1/R2
1
1
9
the methylenic carbon atoms of the pendant arms).
NiL1]+
NiL2]+
136.9 / 47.8b
[
[
99.4(1)
125.0(2)
40.8(2)
0.80
34.2(1)
0.84
98.3 / 30.0b
a
Data obtained at 7.05 T. Standard deviations within parenthesis. SNRs obtained
for TFA using identical experimental conditions.
2
+
Fig 4. CEST spectra of [NiL ] (15 mM) in H
2
O containing 20% acetonitrile (pH
7
, saturation time 10 s) recorded using different saturation powers.
The 19F NMR spectra of the two complexes present a signal
at -59.7 ppm due to the ligand CF groups, which in the case of
NiL ] implies that the rotation about the amide N-C bond of
3
1
+
[
the phenyl group is fast on the NMR time scale. The spectra of
the two complexes show very different linewidths, which
1
9
anticipates distinct F relaxation rates (Fig. 5). This is
confirmed by the longitudinal (R ) and transverse (R
relaxation rates, which were measured at three different
magnetic fields (Table 1, Fig. 5). Both the R and R values
remain constant within experimental error at 7, 9.4 and 11.75
T. The two complexes present virtually identical R /R ratios
Table 1). Both the R and R values are higher for [NiL ] with
1
2
)
1
2
1
2
1
+
(
1
2
2
+
respect to [NiL ] , which is likely associated to a shorter
average Ni···F distance in the former. The experimental data
was analysed by using the standard Solomon-Bloembergen-
Morgan theory of paramagnetic relaxation. The F relaxation
rates at the high fields employed in this study are not affected
2
0
19
2
+
by the relaxation of the Ni electron spin. Thus, the analysis of
1 2
Fig. 5. (a) Top: longitudinal (R , squares) and transverse (R , circles) relaxation rates
1
+
2 +
the experimental data required fitting two parameters: the recorded for [NiL ] and [NiL ] (as the chloride and triflate salts, respectively). The solid
2
98
lines correspond to the fits of the data using Solomon-Bloembergen-Morgan theory. (b)
rotational correlation time 
R
, which was assumed to be
1
9
F NMR spectra (7.05 T, 25 ⁰C) of [NiL ] and [NiL ] . (c) 19F MRI on tube phantoms (15
1
+
2 +
identical for the two complexes, and the Ni···F distances. We
1
+
2 +
mM complex, 7.05 T, RT) of [NiL ] , [NiL ] and TFA (30 mM left tube, 15 mM right
tube). Acquisition parameters: FOV = 32 x 32, MTX = 32 x 32, slice thickness 5 mm, pixel
size 1 mm, 400 L vials.
2
98
obtained a 
R
value of the Ni···F vector of 89 + 10 ps, which
is reasonable considering the size of the complexes. The Ni···F
distances were determined to be 7.28 + 0.42 and 8.72 + 0.5 Å
for [NiL ] and [NiL ] , respectively. The dipolar paramagnetic
relaxation mechanism is proportional to (1/rNiF) , with rNiF
being the Ni···F distance. The rNiF distances estimated by
averaging the (1/rNiF) values observed in the X-ray crystal
structures of [NiL ] and [NiL ] are 7.01 and 9.3 Å,
respectively. Thus, the values obtained from the analysis of
1
+
2 +
We also undertook a 19F MRI study on tube phantoms
using 15 mM solutions of the two complexes. Tubes containing
6
19
trifluoroacetic acid (TFA) with equal F nuclei concentrations
6
1 +
2 +
(
i.e. 30 and 15 mM of TFA relative to [NiL ] and [NiL ] ,
1
+
2 +
respectively) were used for comparative purposes. The tube
2 +
containing [NiL ] resulted in the ‘ghost’ image arising from the
presence of trifluoromethanesulfonate counter anions (see
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above),8 which did not affect the SNR for [NiL ] due to
2 +
F. Tweedle, Radiology, 2015, 275, 630. (d) T. J.ViFerwaAurtmicl,e ODn.liRne.
Ludwig, M. R. Bashir and K. J. Fowler, J. Magn. Reson.
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sufficient difference in the resonance frequency of fluorine
Imaging, 2017, 46, 338.
1
9
atoms in these two molecules. The resulting F MR images
3
(a) S. Cheng, L. Abramova, G. Saab, G. Turabelidze, P. Patel,
M. Arduino, T. Hess, A. Kallen and M. Jhung, J. Am. Med.
Assoc., 2007, 297, 1542; (b) T. H. Darrah, J. J. Prutsman-
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E. Hannigan, Metallomics, 2009, 1, 479.
1
9
confirmed the potential of these complexes as F probes. The
1
+
obtained signal-to-noise ratio (SNR) for [NiL ] after 1 hour
acquisition time was 137, which was 2.8 times higher than that
2
+
of TFA (48). Concurrently, the SNR determined for [NiL ] was
.3 times higher than that of TFA. Obviously, the
4
5
V. M. Runge, Invest. Radiol., 2018, 53, 571.
E. M. Gale, I. P. Atanasova, F. Blasi, I. Ay and P. Caravan, J.
Am. Chem. Soc., 2015, 137, 15548.
3
1
9
paramagnetism of the metal ion affected the F relaxation
times to a significant extent; however, proportional shortening
of both 1 F T
6
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D. Sherry, J. Am. Chem. Soc., 2008, 130, 6; b) S. J. Ratnakar, T.
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Spernyak and J. R. Morrow, J Am Chem Soc., 2012, 134,
9
1
and T
2
resulted in the values that allow fast
repetitions with still sufficient signal, thus giving rise to greater
1
9
SNR values. In turn, these F MRI experiments demonstrated
7
1
+
2 +
advantageous properties of [NiL ] and [NiL ] over the
diamagnetic reference, indicating perspectives for their
1
9
consideration as F MRI contrast agents.
In conclusion, we have reported Ni
2
+
cross-bridged
1
8503.
derivatives that form extremely inert complexes with great
potential for the design of MRI probes. We demonstrated that
functionalisation of the macrocyclic platform with pendant
8
9
J. Ruiz-Cabello, B. P. Barnett, P. A. Bottomley and J. W. Bulte,
NMR Biomed. 2011, 24, 114.
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Z. Tošnerc and J. Kotek, Dalton Trans., 2016, 45, 474; (b) M.
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arms containing amide protons and CF
3
1
groups provides
19
potential for these systems to be used as H/ F probes. The
2
+
19
paramagnetism of the Ni ion allows for a faster F MRI
acquisition thanks to the paramagnetic relaxation
enhancement effect. The paramagnetically shifted resonance 10 (a) K. L. Peterson, K. Srivastava and V. C Pierre, Front. Chem.
2
018, 6, 160; (b) a) K. Srivastava, E. A. Weitz, K. L. Peterson,
M. Marjanska and V. C. Pierre, Inorg. Chem., 2017, 56,
546−1557. (c) K. H. Chalmers, E. De Luca, N. H. M. Hogg, A.
of amide protons promotes the CEST effect safely distant from
bulk water. This work further expands the scope of
applications of the cyclam-based systems, ensuring exciting
forthcoming developments in the field of chemistry of MRI
contrast agents.
Authors R. P.-P., D. E.-G. and C. P.-I. thank Ministerio de
Economía y Competitividad (CTQ2016-76756-P) and Xunta de
Galicia (ED431B 2017/59 and ED431D 2017/01) for generous
financial support. R. P.-P. thanks Ministerio de Economía y
1
M. Kenwright, I. Kuprov, D. Parker, M. Botta, J. I. Wilson and
A. M. Blamire, Chem. Eur. J., 2010, 16, 134.
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Competitividad for a PhD FPI grant (BES-2014-068399) and a 13 (a) R. Smith, D. Huskens, D. Daelemans, R. E. Mewis, C. D.
Garcia, A. N. Cain, T. N. C. Freeman, C. Pannecouque, E. De
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fellowship for a short term stay in Tuebingen (EEBB-I-17-
2213). T.S. thanks the German Academic Exchange Service
DAAD) for the Ph.D. fellowship.
1
(
1
Conflicts of Interest
There are no conflicts to declare.
1
1
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| Chem. Commun., 2016, 00, 1-3
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DOI: 10.1039/C9CC01204D
Table of Contents Entry
Extremely inert paramagnetic nickel(II) complexes based on a cross-bridged cyclam platform
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present response at the H (CEST) and F frequencies.