Photoswitchable Magnetic Resonance Imaging Contrast by Improved Light-Driven Coordination-Induced Spin State Switch

Article abstract of DOI:10.1021/jacs.5b00929

We present a fully reversible and highly efficient on-off photoswitching of magnetic resonance imaging (MRI) contrast with green (500 nm) and violet-blue (435 nm) light. The contrast change is based on intramolecular light-driven coordination-induced spin state switch (LD-CISSS), performed with azopyridine-substituted Ni-porphyrins. The relaxation time of the solvent protons in 3 mM solutions of the azoporphyrins in DMSO was switched between 3.5 and 1.7 s. The relaxivity of the contrast agent changes by a factor of 6.7. No fatigue or side reaction was observed, even after >100 000 switching cycles in air at room temperature. Electron-donating substituents at the pyridine improve the LD-CISSS in two ways: better photostationary states are achieved, and intramolecular binding is enhanced.

Full text of DOI:10.1021/jacs.5b00929

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Communication
Photoswitchable MRI contrast by improved LD-CISSS
Marcel Dommaschk, Morten Peters, Florian Gutzeit, Christian Schütt, Christian Näther,
Frank D. Sonnichsen, Sanjay Tiwari, Christian Riedel, Susann Boretius, and Rainer Herges
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b00929 • Publication Date (Web): 27 Apr 2015
Downloaded from http://pubs.acs.org on May 4, 2015
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Photoswitchable MRI contrast by improved LD-CISSS.
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Marcel Dommaschk, Morten Peters, Florian Gutzeit, Christian Schütt, Christian Näther,
†
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§
§
†
Frank D. Sönnichsen, Sanjay Tiwari, Christian Riedel, Susann Boretius, and Rainer Herges*
†
Otto-Diels-Institut für Organische Chemie, Christian-Albrechts-Universität, Otto-Hahn-Platz 4, 24098 Kiel, Germany
Institut für Anorganische Chemie, Christian-Albrechts-Universität, Otto-Hahn-Platz 6/7, 24098 Kiel, Germany
Clinic for Radiology and Neuroradiology, Arnold Heller Str. 3, 24105 Kiel, Germany
‡
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Supporting Information Placeholder
2
0%.32,33 Our approach to the design of responsive and partic-
ABSTRACT: We present a fully reversible and highly efficient
on-off photo switching of magnetic resonance imaging (MRI)
contrast with green (500 nm) and violet-blue (435 nm) light.
The contrast change is based on the intramolecular Light-
Driven Coordination-Induced Spin State Switch (LD-CISSS)
which was performed with azopyridine substituted Ni-por-
ularly light-controlled CAs is different from the above meth-
ods. We are not controlling the access of the solvent molecules
to the paramagnetic ion, but we are switching the spin state of
transition metal ions between paramagnetic and diamagnetic.
Whereas a Gd complex in the “off-state” with a completely
filled coordination sphere, which blocks water access, still ex-
hibits a residual relaxivity by outer sphere relaxation (through
space magnetic dipol interaction), a diamagnetic transition
metal complex with S = 0 is completely MRI silent. Spin state
switching, therefore, offers the potential to achieve a higher
efficiency in relaxivity control. Contrast switching is very im-
portant in interventional radiology (catheter based surgery
1
phyrins. The T relaxation time of the solvent protons in 3 mM
solutions of the azoporphyrins in DMSO was switched be-
tween 3.5 and 1.7 s. The relaxivity of the contrast agent changes
by a factor of 6.7. No fatigue or side reaction was observed
even after more than 96000 switching cycles under air at room
temperature. Electron donating substituents at the pyridine
improve the LD-CISSS in two ways: Better photo stationary
states are achieved and the intramolecular binding is en-
hanced.
Magnetic resonance imaging (MRI) is one of the most im-
portant, non-invasive tools in diagnostic medicine. As op-
posed to other deep tissue imaging modalities such as com-
puter tomography (CT) or positron emission spectroscopy
34,35
under imaging control).
The change in contrast so far is
obtained by administration of additional CAs each time when
this is required. After multiple injections the CAs accumulate
in the blood circuit to a level where they are harmful and the
contrast change is gradually lost. Light-sensitive CAs have the
advantage that they have to be administered only once and
the contrast can be switched rapidly via an optical fiber
Recently, we developed a very efficient system for switching
the spin state of Ni complexes between diamagnetic (S=0)
and paramagnetic (S=1) with light of two different wave-
lengths.
(
PET) no ionizing radiation is used in MRI examinations and
no radiation damage is induced. To date, more than 200 mil-
lion doses of MRI contrast agents (CAs) have been adminis-
tered to patients worldwide. . Commercially available CAs
2+
1
,2
36,37
3
,4
We now present a systematic improvement of the
are mainly gadolinium(III) chelate complexes. With a spin
of 7/2 these molecules are highly paramagnetic and decrease
the NMR relaxation time of surrounding water protons (or
other NMR active nuclei) which in turn leads to signal en-
hancement in MRI. The majority of clinically used Gd(III) che-
lates are strongly hydrophilic and therefore, after intravenous
injection, the complexes stay mainly in the blood circuit lead-
ing high contrast of blood vessels. Since the MRI signal en-
hancement correlates with the concentration of CAs they pri-
marily increase anatomical contrast. Further physiological in-
formation could be obtained by responsive or “smart” CAs
whose relaxivity (capability of reducing the relaxation time of
surrounding nuclei) is controlled by metabolic parameters.
The design of responsive contrast agents reporting on param-
eters such as temperature, pH or biochemical markers is sub-
ject to intensive research because they are potentially capable
to visualize the site of a disease in an MR image. Research in
this field started in the mid-nineties. Most of the approaches
since then are based on Gd(III) complexes whose relaxivity is
effect and demonstrate that it can be used to switch MRI con-
trast on and off.
Addition of axial ligands to a solution of Ni-porphyrins re-
3
8-41
sults in a coordination-induced spin-state switch (CISSS).
Upon increasing the coordination number (CN) from CN = 4
(no axial ligand, square planar, S = 0) to CN = 5 (one axial lig-
and, square pyramidal, S = 1) or CN = 6 (two axial ligands,
2+
square bipyramidal, S = 1) the Ni ion switches from diamag-
netic (contrast off) to paramagnetic (contrast on). To achieve
light-controlled addition and removal of axial ligands we use
a photochromic azopyridine which is covalently attached to a
Ni-porphyrin. The geometry is designed in such a way that the
pyridine unit coordinates to the Ni ion if the azo group is in
cis configuration, however, intramolecular coordination is not
possible in the trans form. Light of two different wavelengths
is used to isomerize the azo group and to lift the pyridine ring
up and down. For obvious reasons, we coined this approach
the record player design and the process is called light-driven,
coordination-induced spin state switch (LD-CISSS). To
achieve a maximum efficiency in MRI contrast switching,
every step in the cascade of events: photo-isomerization → co-
ordination change → spin switch → MRI contrast change has
to be optimized.
3
+
controlled by controlling the water coordination to the Gd
ion which is the most efficient relaxation mechanism. A num-
ber of CAs were developed with response to proteins and en-
5-11
12,13
14-20
2+ 21-26
zyms, carbohydrates, pH value,
and ions like Ca ,
2+ 27-29
+/2+ 30
+ 31
Zn ,
Cu
, and K . A less intensively investigated stim-
Even a perfect photo conversion between trans and cis iso-
mers does not imply a complete change in coordination num-
bers. Incomplete intramolecular binding in the cis form, and
ulus is light. Functionalization of Gd(III) chelates with photo-
chromic spiropyrans gave rise to contrast changes of about
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intermolecular coordination of the trans isomer, particularly
rins obviously is completely different from the usual azoben-
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at higher concentrations, are limiting the efficiency. Previous
work on our prototype system has shown, that the intramo-
zene isomerization pathway. Recently, a theoretical investiga-
tion suggested an excitation of the porphyrin and a subse-
3
4
42
lecular coordination of the cis configuration is not complete.
quent thermal isomerization of the azopyridine unit. To de-
1
Obviously, there is a non-binding conformation of the cis iso-
mer with the azopyridine unit pointing away from the porphy-
rin ring which is in fast equilibrium (on the NMR time scale)
termine the trans-cis conversion rate we used H NMR spec-
troscopy. The protons at the phenyl ring in meta position to
the azo group resonate between 6.5 and 6.8 ppm for all four
derivatives. Signals for cis and trans isomer are well separated
so that the trans/cis ratio could be determined by integration
of the corresponding signals (see SI). Although the cis isomer
3
5-37
with the binding conformation (Figure 1).
It is known that
the association constant of 4-substituted pyridines follows a
4
0
Hammett relationship. To improve the intramolecular coor-
dination we therefore introduced electron donating groups
1
has decreased H relaxation times due to its paramagnetism,
0
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(
Me and OMe) at the 4-position of the pyridine unit (synthe-
the integral is still representative for the amount of the iso-
mers which was demonstrated by comparison with external
signals (see SI). Photochemical conversion of the trans to the
cis isomer (Figure 2) follows the same trend as the coordina-
tion of the cis isomer (Figure 1). Upon irradiation with light of
500 nm the photostationary state increases from 62% (R=Cl)
to >95% (R=OMe) conversion to the cis form. Back-reaction
to the trans form upon irradiation with 435 nm is quantitative
within the detection limit of NMR (<5% remaining cis). Thus,
overall conversion from the diamagnetic to the paramagnetic
state improved considerably by introduction of the methoxy
substituent (1a: 85%) compared to the parent system (1c:
48%).
ses see SI).
To quantify intramolecular binding, the chemical shifts
1
of pyrrole protons in H NMR spectra of 1a-d were compared.
We have previously shown that coordination and de-coordi-
nation of axial ligands in Ni-porphyrins is fast on the NMR
time scale. The chemical shift of the pyrrole protons of record
player 1c in non-coordinating solvents is 8.9 ppm and 53 ppm
in pure pyridine-d5 (complete axial coordination). The aver-
age chemical shift therefore is an accurate measure of the ratio
of diamagnetic and paramagnetic Ni-porphyrins in solution.
Acetone-d was chosen as the solvent for our experiments be-
6
cause of its low coordination power as an axial ligand and the
high solubility of 1a-d in acetone (Figure 1).
Figure 2. Photo stationary states (% cis isomer) and per-
centage of paramagnetic Ni ions upon irradiation of solutions
of 1a-d in acetrone-d at 20° C with light of 435 and 500 nm.
6
The cis-trans-ratio and the percentage of paramagnetic Ni
ions were determined by NMR spectroscopy (for details see
text).
Figure 1. Equilibrium between the coordinated cis-1para and
the non-coordinated form cis-1dia (top). From the chemical
The systems were tested regarding their long term switching
stability. The methoxy substituted derivative 1a does not ex-
hibit any fatigue after more than 96000 switching cycles at
room temperature under air (Figure 3). To test the stability of
compounds 1a-1c in a biological relevant environment we
treated them with a 10 mM solution of glutathione in acetoni-
trile/PBS buffer (1:1). No reduction of the azo function and no
6
shifts of the pyrrole protons (av. shift) in acetone-d (bottom
2+
left) the percentage of paramagnetic Ni (cis-1para) was calcu-
lated (bottom right).
The amount of paramagnetic cis isomer (cis-1para) depends
strongly on the 4-pyridine substituent (R). Electron donating
groups increase the amount of cis-1para drastically (from 74%
for R=H to 89% for R=OMe). Electron withdrawing groups
degradation of the switching efficiency was observed which
43-46
are
requirements
for
in
vivo
applications.
(
R=Cl) have a contrary effect (Figure 1). Thus, the switching
efficiency to the paramagnetic state has been strongly im-
proved by introduction of the OMe group at the 4-position of
the pyridine.
While it is obvious that the pyridine substituent affects
the axial binding to the Ni-porphyrin we surprisingly observed
an improved photochemical trans-cis conversion as well. Irra-
diation of the trans isomers with light of 500 nm (Q-bands of
trans azo-porphyrin 1a-d: 523 and 557 nm) is most efficient to
convert the trans to the cis isomer. This is surprising because
the -* excitation which induces trans-cis isomerization in
azobenzenes and azopyridines has a much shorter wavelength
Figure 3. Long-term switching stability of 1a (5.0 M,
MeCN, 20 °C) during alternating irradiation with 500 nm and
(
~320 nm). The isomerization mechanism in our azo-porphy-
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4
35 nm. The UV-vis absorption at 422 nm is plotted as a func-
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tion of the number of switching cycles.
Table 1. Relaxivities of 1a-c in a mixture of 99% DMSO-d
6
and 1% DMSO measured in a 200 MHz NMR spectrometer.
-1 -
Crystals of the cis isomer of 1b (R=Me) suitable for X-ray
structure determination were obtained (Figure 4, left). The
nickel center is complexed in a distorted octahedral coordina-
tion geometry. The equatorial plane is formed by the porphy-
rine nitrogen atoms with bond length ranging from 2.03 to
1
R / mM s
R (#)
500 nm
0.159
0.155
435 nm
0.045
0.029
0.0.18
MeO (1a)
Me (1b)
H (1c)
0.121
2.05 Å. The axial positions are occupied by the pyridine nitro-
gen atom of the azopyridine and the oxygen atom of a metha-
nol molecule with longer distances of Ni-N = 2.18 Å and
Ni-O = 2.27 Å. The nickel center is situated almost exactly in
the porphyrin plane with a deviation of 0.08 Å. The X-ray
structure is in good agreement with the DFT (PBE/SVP) opti-
mized structure (Figure 4, right). The RMSD (route main
square deviation) is 0.31 Å (for details see SI).
The relaxivity of the trans isomers (1a-c) after irradiation
with 500 nm increases by factor of 3.5, 5.3 and 6.7. Upon irra-
diation with 435 nm the relaxivity drastically decreases again
but is different from zero which is probably due to some re-
sidual paramagnetism due to intermolecular coordination.
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The absolute values of the relaxivity R is lower by a factor of
about 25 compared to standard Gd-contrast agents which is
mainly due to the lower magnetic moment (Ni(II): S = 1,
Gd(III): S = 7/2). We determined relaxivity of gadobutrol in
-1 -1
DMSO-d
literature (see SI).
6
to be 3.75 mM s which in good agreement with the
47,48
To realize the switching in a physiolog-
ical medium we will attach glycerol dendrimers to the meso-
pentafluorophenyl substituents by nucleophilic aromatic sub-
stitution. It was already shown that this concept is applicable
Figure 4. Crystal structure of cis-1b (left) and overlay of the
crystal structure (red) and calculated structure (blue,
PBE/SVP) (right).
41
for symmetric porphyrins. We performed cell tests and
proved that the dendronized water soluble Ni-porphyrin does
not influence cell activity at physiologically relevant concen-
trations (see SI).
As a further step towards application of the switchable con-
trast agents we performed the photo switching in a MRI scan-
ner to monitor the magnetic switching in situ. Light of 530 and
The application of the record player molecules 1a-c as light-
switchable contrast agents was investigated by MRI (3 and 7
Tesla) and independently by NMR relaxation time measure-
ments (200 MHz NMR). Switching between the diamagnetic
and paramagnetic state in a homogenous solution of 1a-d al-
lows to switch the relaxation time of the solvent protons and
thus to switch MRI contrast using violet-blue and green light.
Figure 5 shows the MRI contrast of 3 mM solutions of 1a-d in
DMSO after irradiation with light of 435 and 500 nm. As ex-
pected, the increased conversion rate to the paramagnetic
state (1c < 1b < 1a) also leads to an increase of the signal in the
MRI images (Figure 5). The diamagnetic trans state is MRI si-
lent in all cases.
4
05 nm was applied by an optical fiber coupled to monochro-
matic LEDs (light intensity at the fiber outlet ~35 and 75 mW).
A coaxial NMR tube with a 3 mM solution of record player 1c
in DMSO was irradiated. The on-off switching of the MRI con-
strast is shown in Figure 6 (right) (see also supporting video
(
web enhanced object)).
Figure 6. Experimental setup for the contrast switching in
a 7 T MRI scanner (left). A 3 mM solution of 1c was irradiated
with 530 nm and 405 nm light, and MRI images were recorded
after irradiation (right). A video which demonstrates contrast
switching is available (web enhanced object).
Figure 5. 3 T MR-image of 3 mM solutions of 1a-c irradiated
with 435 nm and 500 nm. For details see supporting infor-
mation.
The efficiency of paramagnetic ions to shorten the relaxa-
tion time of solvent protons, normalized by their concentra-
tion, is called relaxivity (R in mM s ). R
ivities corresponding to the longitudinal (T
relaxation time (T ). In the following we only present results
for T and R because there are no significant differences to T
and R in homogeneous solutions (see SI). The T relaxivity
In summary, we have developed a highly efficient, light-re-
sponsive molecular, magnetic switch. Green (500 nm) and vi-
olet-blue (435 nm) light was used to switch the relaxation time
of solvent protons in a 3 mM solution by a factor of more than
-1 -1
1
and R
2
are the relax-
1
) and transversal
2
1
two, and the relaxivity (R ) of the contrast agent changes by a
1
1
2
factor of up to 6.7. The change in contrast is clearly visible in
a clinical MRI scanner. Contrast control is based on a cascade
of events which includes: photo-isomerization of an
2
1
was determined by relaxation time measurements at different
contrast agent concentrations. The experiments were per-
formed with 1a-c in a mixture of 99% DMSO-d
2+
azopyridine ligand → coordination change at Ni → spin
6
and 1% DMSO
switch → MRI contrast change. The system was optimized in
in a 200 MHz (4.7 T) NMR-spectrometer (Table 1, SI).
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such a way that each step is close to quantitative. No side re-
action or fatigue was detected after more than 96000 switch-
ing cycles. The metastable cis form (contrast-on state) has a
half-life of more than 1 year at room temperature. Our Light-
Driven Coordination-Induced-Spin-State-Switch (LD-CISSS)
approach has the potential to provide the basis for the devel-
opment of a number of interesting applications including the
design of temperature or pH responsive contrast agents for
MRI. The latter would be useful to detect tumors because they
exhibit a higher temperature and a lower pH than surrounding
tissue.
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ASSOCIATED CONTENT
Supporting Information.
Chem. 2002, 41, 4018.
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(
Experimental procedures and spectral data for all new com-
pounds, details of computational studies, crystallographic
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http://pubs.acs.org.”
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AUTHOR INFORMATION
Corresponding Author
rherges@oc.uni-kiel.de
(
Perkin Trans. 2 2001, 1840.
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(
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0788.
30) Que, E. L.; Gianolio, E.; Baker, S. L.; Wong, A. P.; Aime, S.;
The authors declare no competing financial interest.
1
(
ACKNOWLEDGMENT
The authors gratefully acknowledge funding from the collab-
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