More Than 12 % Polarization and 20 Minute Lifetime of 15N in a Choline Derivative Utilizing Parahydrogen and a Rhodium Nanocatalyst in Water

Article abstract of DOI:10.1002/anie.201804185

Hyperpolarization techniques are key to extending the capabilities of MRI for the investigation of structural, functional and metabolic processes in vivo. Recent heterogeneous catalyst development has produced high polarization in water using parahydrogen with biologically relevant contrast agents. A heterogeneous ligand-stabilized Rh catalyst is introduced that is capable of achieving ¹⁵N polarization of 12.2±2.7 % by hydrogenation of neurine into a choline derivative. This is the highest ¹⁵N polarization of any parahydrogen method in water to date. Notably, this was performed using a deuterated quaternary amine with an exceptionally long spin-lattice relaxation time (T₁) of 21.0±0.4 min. These results open the door to the possibility of ¹⁵N in vivo imaging using nontoxic similar model systems because of the biocompatibility of the production media and the stability of the heterogeneous catalyst using parahydrogen-induced polarization (PHIP) as the hyperpolarization method.

Full text of DOI:10.1002/anie.201804185

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Accepted Article
Title: Over 12% Polarization and 20 Minute Lifetime of 15N on Choline
Derivative Utilizing Parahydrogen and Rh Nanocatalyst in Water
Authors: Jeffrey McCormick, Sergey Korchak, Salvatore Mamone,
Yavuz Ertas, Zhiyu Liu, Luke Verlinsky, Shawn Wagner,
Stefan Gloeggler, and Louis Bouchard
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804185
Angew. Chem. 10.1002/ange.201804185
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10.1002/anie.201804185
Angewandte Chemie International Edition
COMMUNICATION
Over 12% Polarization and 20 Minute Lifetime of 15N on Choline
Derivative Utilizing Parahydrogen and Rh Nanocatalyst in Water
Jeffrey McCormick[a], Sergey Korchak[b,c], Salvatore Mamone[b,c], Yavuz N. Ertas[a,d], Zhiyu Liu[a], Luke
Verlinsky[a], Shawn Wagner[e], Stefan Glöggler* [b,c], Louis-S. Bouchard*[a.d]
The inherently low sensitivity of magnetic resonance
methods limits the scope of chemical and biological investigations
in clinical contexts. This has motivated recent advancements in
Abstract: Hyperpolarization techniques are key to extending the
hyperpolarization techniques capable of generating several
capabilities of MRI for the investigation of structural, functional and
orders of magnitude signal enhancements with contrast agents
metabolic processes in vivo.
Recent heterogeneous catalyst
such as metabolites. Dissolution dynamic nuclear polarization (d-
DNP) can generate large polarizations on injectable contrast
development has produced high polarization in water using
parahydrogen with biologically relevant contrast agents. Here we
agents and has shown great promise in medical application[1–4]
,
introduce
a novel heterogeneous ligand-stabilized Rh catalyst
even though DNP requires high capital equipment investment and
requires several hours to produce a polarized sample prohibiting
concepts like continuous multiple infusions[5]. An alternative
approach of hyperpolarization uses the singlet spin state isomer
of hydrogen known as parahydrogen (para-H2) to generate
polarization via PHIP[6–8] and Signal Amplification by Reversible
Exchange (SABRE)[9]. These techniques are significantly more
cost-effective as 100% enriched para-H2 can be easily generated
by flowing H2 gas over a catalyst at low temperatures and stored
at room temperature. Additionally, the equipment has a lower
base cost since only low magnetic fields are required eliminating
the high acquisition cost of a superconducting magnet and
maintenance.
capable of achieving 15N polarization of 12.2 ± 2.7% by hydrogenation
of neurine into a choline derivative. This is the highest 15N polarization
of any parahydrogen method in water to date. Notably, this was
performed using a deuterated quaternary amine with an exceptionally
long spin-lattice relaxation time (T1) of 21.0 ± 0.4 minutes. These
results open the door to the possibility of 15N in vivo imaging using
nontoxic similar model systems because of the biocompatibility of the
production media and the stability of the heterogeneous catalyst using
parahydrogen-induced polarization (PHIP) as the hyperpolarization
method.
The implementation of solution-state PHIP techniques
which employs effective homogeneous catalysts in organic
solvents and water pose concerns over the bio-toxicity of the
hyperpolarized product mixtures[10] and has motivated
heterogeneous alternatives capable of high aqueous polarization.
Though high 13C polarizations (>3%) have recently been shown
by labile transfer of cleavable [1-13C]pyruvate derivatives into pure
water using homogeneous catalyst[11], metal degradation was
observed in addition to concerns of chemical stability in the
presence of unprotected nitrogen groups, necessitating further
method optimization. Excellent advances have been made with
efficient 15N polarization using the PHIP variants SABRE and
SABRE-SHEATH, however these methods have thus far
[a]
J McCormick, M. Sc, Dr. Yavuz N. Ertas, Zhiyu Liu, Luke Verlinsky.,
Prof. L.S. Bouchard
Department of Chemistry and Biochemistry, University of California
at Los Angeles, 607 Charles E Young Drive East, Los Angeles,
California 90095-1569, USA
[b]
[c]
Dr. Sergey Korchak, Dr. Salvatore Mamone, Dr. Stefan Glöggler
Research Group for NMR Signal Enhancement
Max Planck Institute for Biophysical Chemistry
Am Fassberg 11, D-37077 Göttingen, Germany
Dr. Sergey Korchak, Dr. Salvatore Mamone, Dr. Stefan Glöggler
Center for Biostructural Imaging of Neurodegeneration
Von-Siebold-Str. 3A, D-37075 Göttingen, Germany
E-mail: stefan.gloeggler@mpibpc.mpg.de
investigated compounds with subclinical 15N polarizations[12]
,
optimization in organic solvents[13,14], and limited development of
heterogeneous catalysts[15,16]. While PHIP has been investigated
in vivo[17–21], clinical applications require the production of the non-
toxic and preferably pure sterile product; a heterogeneous
catalyst can be removed from the mixture after polarization
[d]
[e]
[f]
Dr. Y. N. Ertas, M. Sc., Prof. L.-S. Bouchard
Department of Bioengineering, University of California at Los
Angeles, 607 Charles E Young Drive East, Los Angeles, California
90095-1569, USA
enhancement creating
a
pure aqueous solution of the
hyperpolarized compound of interest[22]. Transition metal particles
based on Pt, Pd and Rh have been previously reported as
capable heterogeneous catalysts for PHIP with a variety of
substrate molecules, but none have been used for in vivo imaging
Dr. S. Wagner
Biomedical Imaging Research Institute, Cedars-Sinai Medical
Center, 8700 Beverly Blvd, Davis Building G149E, Los Angeles,
California 90048, USA
because of the reduced polarization values[23–25]
.
In this work, we introduce an N-acetylcysteine (NAC)
stabilize metal using rhodium (Rh) to produce the new
heterogeneous nanoparticle, NAC@Rh. This catalyst allows for
efficient polarization of quaternary 15N nuclei with long relaxation
times. NAC-stabilized metal nanoparticles have recently been
Prof. L.-S. Bouchard
The Molecular Biology Institute, Jonsson Comprehensive Cancer
Center, California NanoSystems Institute, University of California at
Los Angeles
E-mail: louis.bouchard@gmail.com
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10.1002/anie.201804185
Angewandte Chemie International Edition
COMMUNICATION
demonstrated to generate 1H polarizations exceeding 1% in
ESOTHERIC[39] was employed for polarization transfer to 15N.
This sequence is well-suited for NETMA as it is able to transfer
the nascent para-H2 longitudinal two-spin order into observable
in-phase heteronuclear magnetization in weakly coupled spin
water[26]
, these polarizations are measured values without
compensation for signal decay loss from transit to the
spectrometer. Since 1H polarization decays within seconds owing
to short longitudinal spin relaxation times T1, the preservation of
polarization via transfer to nearby nuclei such as 13C, which have
a T1 on the order of a minute, or 15N, which can have T1 on the
systems[39]. This is the first reported method for achieving high 15
N
hyperpolarization via pulse transfer with aqueous PHIP[40]. The
relevant precursors and products used in this work as well as the
relevant J-couplings are shown in Figure 1.
order of tens of minutes, is essential for clinical utilization[27]
.
Because of the very long relaxation time of 15N, it could have a
distinct advantage over for 13C for clinical applications. Thus, the
An essential component to advancing PHIP methodologies
for in vivo applications is the ability to store nascent polarization
hyperpolarization of 15N nuclei in contrast agents is of high interest. as long-lived heteronuclear longitudinal magnetization to allow
Since the gyromagnetic ratios (γ) of 15N and 13C are substantially
lower than 1H, imaging resolution will be inherently lower with
comparable gradients, but strategies to overcome this by pulse
detection of the enhanced signal after delivery to the target
tissues. Unlike previous homogeneous catalysts i.e. Rh[1,4-
Bis(diphenylphosphino)butane](norbornadiene)BF4
and
its
transfer back to nearby 1H before acquisition have been shown[28]
.
derivatives[10,33,41,42], heterogeneous hydrogenations occurring on
a metal surface can lead to randomization of the hydrogen spins.
Ligand design not only allows dispersion and particle size control
but favors pairwise para-H2 addition via restricting hydride
diffusion during hydrogenation, thus preserving the spin order of
para-H2 and hence observable polarization. Cysteine derivatives
provide convenient thiol and amine groups which coordinate
strongly to transition metals and form stable colloids, as well as
suspend in water. Rh has been used in traditionally homogeneous
PHIP catalysis and recently in heterogeneous catalysts (HET-
While 13C polarization levels exceeding 50% are readily
achieved[1,29] in various injectable contrast agent systems in d-
DNP, 15N polarization levels obtained by d-DNP remain limited
due to the considerably lower gyromagnetic ratio γ of 15N. Only
recently large 15N polarization were achieved for the partially-
deuterated quaternary amine trimethylphenylammonium (TMPA)
by cross polarization DNP (CP-DNP)[30]. The use of protonated
compounds to achieve high polarization levels in CP-DNP
typically results in 15N relaxation times[22] shorter than in fully
1
deuterated analogs. While 60-90% starting H polarization was
PHIP)[22,23]
polarization than Ir, Pt and Pd systems in similar immobilized
materials[43]
, where it has been shown to produce higher
used for polarizing 15N nuclei via cross polarization, only P15N
~
17% was obtained after dissolution[30]
.
.
To demonstrate the effectiveness of NAC@Rh in aqueous
PHIP with respect to prior work, 13C hyperpolarization in two
compounds is investigated: the deuterated angiography contrast
agent 1-13C-hydroxyethyl propionate-d3 (HEP)[31] and the
metabolite derivative ethyl acetate (EA) upon hydrogenation of
their respective precursors 1-13C-hydroxyethyl acrylate-d3 (HEA)
and vinyl acetate (VA) with natural abundance 13C. Enhancement
of 13C on HEP is observed upon transfer of nascent proton
PHIP spectra for all compounds investigated are shown in
Figure 2 and polarization levels are summarized in Table 1. The
polarization method used for each compound was match to the
polarization to carbon via PH-INEPT+,
a well-established
polarization transfer pulse sequence for PHIP[32]. Polarization
1
transfer from H to 13C after (para)-hydrogenation of VA into EA
via field cycling between B0~50 μT (Earth magnetic field) and
B0<0.1 μT inside a μ-metal chamber is also demonstrated.
Unsaturated sidearm groups on acetate derivatives can be
cleaved following polarization transfer to produce pure acetate[33]
,
a
metabolite currently used in metabolic imaging[34]
. To
investigate hyperpolarization of 15N, a nucleus found in many
valuable metabolic probes, the deuterated precursor compound
15N-neurine-d12
is
available,
producing
d12-15N-ethyl
Figure 1. Reaction mechanisms of HEA, neurine and VA hydrogenation. JAA,
trimethylammonium (NETMA) upon hydrogenation, a structural
analog of choline. Choline has previously been investigated as a
metabolic probe by d-DNP[35] and positron emission tomography
(PET)[36] due to its role in cellular phospholipid metabolism and
has been used to probe upregulated choline kinase expression in
malignant tissues[37] and other metabolic information[38]. However,
production of hyperpolarized choline from the precursor substrate
has not been demonstrated, likely because the tautomerization
between the keto and enol state prevents adequate
hydrogenation.
JAX and JA’X values are considered in polarization transfer strategy from 1
to 13C and 15N.
H
methods available to us that has been used in past publications[26]
and the scalar coupling[33] to achieve detectable polarization.
Following application of the ESOTHERIC pulse, P15N of 12.2 ±
2.7% shown in Fig 2c) and 2d) was observed with NETMA,
representing a 12.5-fold improvement over the highest previously
recorded 15N PHIP polarization of 15N-propargylcholine using a
homogeneous catalyst[44], and a 186-fold improvement over
previous aqueous HET-PHIP values[22]. Transfer to 13C on HEP
via PH-INEPT+ and EA via field cycling yielded P13C of 3.2 ± 0.3%
and 1.3 ± 0.3% respectively, representing 2.67-fold and 6.5-fold
After significant 1H polarization was observed following
neurine hydrogenation with NAC@Rh (5.4 ± 0.6%), a recently
demonstrated
heteronuclear
transfer
sequence,
titled
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10.1002/anie.201804185
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COMMUNICATION
improvements
over
previous
aqueous
HET-PHIP
The 15N environment of NETMA is particularly well-suited for
storing polarization in the form of longitudinal magnetization. The
deuteration of the NETMA product contributes to long methyl and
methylene 1H T1 times (11.7 s and 22.5 s, respectively), shown in
Table 1. This allows long 1H polarization buildup times during
para-H2 bubbling before polarization transfer as well as
particularly long 15N T1 relaxation times. A previous 15N PHIP
investigation of NETMA assessed the 15N T1 at 493 seconds (field
strength of 9.4T) by fitting the data to polarization decay without
compensation for the 10° sampling pulses[22]. Investigation shown
in Figure 3 by inversion recovery reveals a T1 of 1259 ± 22
seconds (21.0 ± 0.4 min) under inert conditions and only a slight
drop to 1003 ± 10 seconds (16.7 ± 0.2 min) under air atmosphere
at 14T. This allows a system where large 15N polarization is
generated, then separated from the catalyst and injected while still
retaining over 50% of its original intensity after 14 minutes, a
substantial benefit for medical translation.
investigations[26]
. Thus the NAC@Rh effectiveness is not
exclusive to 15N and demonstrates a greater overall utility than
previous metal nanoparticle catalysts across PHIP polarization
methods.
These results also highlight a key advantage for HET-PHIP,
which is the stability of metal surfaces used for PHIP of
nitrogenous compounds. Because nitrogen groups are excellent
electron donors to transition metals, homogeneous catalysts often
undergo rapid degradation as alkenes are out-competed by
nitrogen groups forming inactive complexes. Upon investigation
of NETMA formation using
5 mM homogeneous Rh[1,4-
Bis(diphenylphosphino]butane)(cyclooctadiene)BF4 catalyst, less
than 1% 1H polarization is observed in addition to discolored
precipitate forming in reaction tubes. Despite generally higher
turnover frequency (TOF), a measurement of hydrogenation rate,
homogeneous complexes are unable to polarize 15N efficiently, as
is evidenced by unprecedented 1H polarization of an unprotected
amino acid recently reported with a heterogeneous catalyst[26]
.
Figure 3. Inversion recovery plot of NETMA 15N in D2O yielding a) 21.0 ± 0.4
minute and b) 16.7 ± 0.2 minute longitudinal relaxation (T1) under inert and air
atmospheres, respectively.
High polarization levels on 15N were obtained by using the
ESOTHERIC pulse sequence which is suited for transferring the
nascent 1H polarization to a heteronucleus in systems where the
added proton pair is a) weakly coupled and b) asymmetrically
coupled to the heteronucleus. Since this applies in NETMA,
ESOTHERIC can theoretically transfer close to 95% spin order
transfer (SOT) from two spin longitudinal order of protons after
(para)-hydrogenation to the target nucleus (i.e. 15N). A more
detailed explanation of the polarization transfer mechanism can
be found elsewhere[39]. In traditional PASADENA experiments at
Figure 2. Pulse diagram for a) PH-INEPT+ applied to HEP with t1 = 69.8 ms
and t2 = 38.9 ms in agreement with previous work[45] and b) Single 13C scan of
HEP following pulse (red) and single 90° scan of reference 100 mM 13C pyruvate
solution (blue) with vertical scaling. c) ESOTHERIC pulse using timings ΔA = ΔC
= 172.4 ms and ΔB = 83 ms corresponding to couplings JAA’=6.0 Hz, JAX=-0.5
Hz and JA’X=2.93 Hz applied to NETMA following hydrogenation and d) Single
15N scan of NETMA following application of ESOTHERIC pulse sequence (red)
and single reference 90° scan of 2 M 15N-urea solution (blue) with vertical
scaling. e) Schematic of field cycling transport out of zero field over 5 seconds
following EA hydrogenation at Earth field consistent with previous reports[26,33]
before insertion into the magnet and f) Single 90° 13C scan of EA following
transport out of zero field (red) and inlet thermal spectrum after 512 scans (blue)
with vertical scaling. Natural abundance vinyl acetate was used (13C, 1.1%). All
experiments performed with 1 mM precursor concentration.
1
high field, initially a 45° pulse is applied to detect the H signal,
achieving a theoretical maximum of 50% SOT, as investigated
elsewhere[45]. After a 45° pulse was used to detect the 1H signal,
P1H=5.4 ± 0.6% was observed here in NETMA, this is thus half the
spin-order polarization. Application of the ESOTHERIC sequence
yields P15N=12.2 ± 2.7%, showing that within the error, nearly
unitary SOT is achievable as observable heteronuclear
polarization. To our knowledge, this represents the most efficient
15N transfer obtained with PHIP at high field.
Table 1 also outlines TOF rates for each contrast agent
investigated. Dispersible colloid catalysts tend to suffer activity
loss due to surface coverage of ligand in place of potential
catalytic sites, typically yielding a much lower TOF than
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10.1002/anie.201804185
Angewandte Chemie International Edition
COMMUNICATION
heterogeneous catalysts capable of robust polarization. TOF for
HEP using NAC@Rh shows 1.67-fold and 3.31-fold improvement
over previous NAC@Pd and LCys@Pd catalyst systems
respectively under identical experimental conditions. This
represents the ability to generate 5.52 mM of HEP in the 15 s
required to hydrogenate using a small para-H2 volume in an NMR
tube and apply transfer polarization methodologies. Future work
at higher generated product concentrations is still needed.
Keywords: rhodium nanoparticles • hyperpolarization •
parahydrogen-induced polarization • polarization transfer •
heterogeneous catalysis
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Acknowledgements
The authors acknowledge support from the National Science
Foundation (NSF) (research grants CHE-1153159, CHE-
1508707, equipment grant CHE-1048804), the Arnold and
Mabel Beckman Foundation, the Jonsson Comprehensive
Cancer Center Foundation at UCLA, the Max Planck Institute for
Biophysical Chemistry and the Stefan Hell Research Fellowship
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10.1002/anie.201804185
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High Polarization in Water: By using
a heterogeneous nanoparticle catalyst
and efficient pulse sequence, the
observation of 15N nuclear-spin
polarization in excess of 12% in a
choline derivative are demonstrated in
water by parahydrogen-induced
polarization (PHIP). A very long T1
relaxation of over 20 minutes is also
observed, as well as versatility with
previous PHIP methods and target
nuclei (i.e., 13C), opening new
J. McCormick, S. Korchak, S. Mamone,
Y.N. Ertas, Z. Liu, L. Verlinsky, S.
Wagner, S. Glöggler*, L.-S. Bouchard*
Page No. – Page No.
Title
Over 12% Polarization and 20 Minute
Lifetime of 15N on Choline Derivative
Utilizing Parahydrogen and Rh
Nanocatalyst in Water
applications for medical MRI.
This article is protected by copyright. All rights reserved.