Efficient Synthesis of Molecular Precursors for Para-Hydrogen-Induced Polarization of Ethyl Acetate-1-13C and beyond

Article abstract of DOI:10.1002/anie.201600521

A scalable and versatile methodology for production of vinylated carboxylic compounds with ¹³C isotopic label in C1 position is described. It allowed synthesis of vinyl acetate-1-¹³C, which is a precursor for preparation of ¹³C hyperpolarized ethyl acetate-1-¹³C, which provides a convenient vehicle for potential in vivo delivery of hyperpolarized acetate to probe metabolism in living organisms. Kinetics of vinyl acetate molecular hydrogenation and polarization transfer from para-hydrogen to ¹³C via magnetic field cycling were investigated. Nascent proton nuclear spin polarization (%P_H) of ca. 3.3 % and carbon-13 polarization (%P_13C) of ca. 1.8 % were achieved in ethyl acetate utilizing 50 % para-hydrogen corresponding to ca. 50 % polarization transfer efficiency. The use of nearly 100% para-hydrogen and the improvements of %P_H of para-hydrogen-nascent protons may enable production of ¹³C hyperpolarized contrast agents with %P_13C of 20-50 % in seconds using this chemistry.

Full text of DOI:10.1002/anie.201600521

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201600521
German Edition: DOI: 10.1002/ange.201600521
Isotopic Labeling
Efficient Synthesis of Molecular Precursors for Para-Hydrogen-
13
Induced Polarization of Ethyl Acetate-1- C and Beyond
Roman V. Shchepin, Danila A. Barskiy, Aaron M. Coffey, Isaac V. Manzanera Esteve, and
Eduard Y. Chekmenev*
Abstract: A scalable and versatile methodology for production
of vinylated carboxylic compounds with C isotopic label in
C1 position is described. It allowed synthesis of vinyl acetate-1-
PHIP may potentially become an ultra-fast and low-cost
hyperpolarization technique for affordable production of
multiple doses of HP contrast agents within minutes.
13
[8]
1
3
13
C, which is a precursor for preparation of C hyperpolarized
However, unlike d-DNP, the PHIP technique relies on the
1
3
ethyl acetate-1- C, which provides a convenient vehicle for
potential in vivo delivery of hyperpolarized acetate to probe
metabolism in living organisms. Kinetics of vinyl acetate
molecular hydrogenation and polarization transfer from para-
pairwise addition of para-hydrogen (para-H ) to an unsatu-
2
rated precursor usually followed by polarization transfer from
13
nascent protons to C centers, with substantially longer P
[
9]
decay times (T ) required for in vivo applications. While
1
1
3
13
hydrogen to C via magnetic field cycling were investigated.
a number of metabolic C HP contrast agents have been
Nascent proton nuclear spin polarization (%P ) of ca. 3.3%
developed for in vivo applications with %P
ꢀ 10% in
H
13C
[
2e,10]
and carbon-13 polarization (%P13C) of ca. 1.8% were achieved
in ethyl acetate utilizing 50% para-hydrogen corresponding to
ca. 50% polarization transfer efficiency. The use of nearly
aqueous medium (e.g. succinate
and phospholacta-
), PHIP remained a relatively restricted technology
because of the chemical challenge of inserting para-H
[3b,11]
te
2
13
1
00% para-hydrogen and the improvements of %P of para-
adjacently to C in molecular frameworks to yield metabol-
ically relevant contrast agents: for example, acetate, pyruva-
H
13
hydrogen-nascent protons may enable production of
C
[11a]
hyperpolarized contrast agents with %P13C of 20–50% in
seconds using this chemistry.
te.
Recently PHIP using side arm hydrogenation (SAH) was
[12]
demonstrated, in which para-H is added into vinyl moiety,
2
[
1]
H
yperpolarized (HP) magnetic resonance is a rapidly
and para-H -derived polarization is transferred to carboxylic
2
[2]
13
growing field, which enables real-time metabolic imaging.
This is possible because nuclear spin polarization (P) of long-
lived (on the order of a minute or more) C sites in
biologically relevant molecules can be enhanced transiently
by 4–8 orders of magnitude to the order of unity or 100%.
Dissolution dynamic nuclear polarization (d-DNP) is one
of the leading hyperpolarization technologies, which has
advanced into clinical trials, and its success has been largely
driven by a wide range of biomolecules amenable for efficient
hyperpolarization. The alternative hyperpolarization tech-
nique of para-hydrogen induced polarization (PHIP) has
two advantages over d-DNP: 1) fast production speed of
C atom. This is fundamentally possible, because in PHIP-
13
SAH the C atom is hyperpolarized by nascent protons three
13
3
4
[12,13]
and four chemical bonds away using J
and J
H–13C H–13C
2
3
rather than the J
approach.
and J
in the conventional PHIP
H–13C
H–13C
[
3]
[9,14]
As a result, PHIP-SAH significantly expands
[
3a]
the reach of amenable-to-hyperpolarization biomolecules,
13
13
including ethyl acetate-1- C, ethyl pyruvate-1- C, and poten-
tially many others. Ethylation is not necessarily a drawback,
because the produced HP contrast agent can be de-pro-
[4]
[12]
tected, or used directly, because ethylation of carboxylic
[5]
[10b]
[15]
acids leads to better cellular
and brain uptake.
The
uptake in the brain is especially relevant to ethyl acetate,
because acetate is one of a few metabolites directly utilized by
[6]
under 1 min versus tens of minutes to several hours, and 2) it
is significantly less instrumentation demanding. Therefore,
[
7]
[16]
the brain as a fuel source.
Despite the potential of PHIP-SAH to revolutionize
molecular imaging, it is faced with two fundamental chal-
lenges. First, an efficient synthesis of vinylated 1- C-carbox-
[
*] Prof. R. V. Shchepin, Dr. D. A. Barskiy, Dr. A. M. D. Coffey,
Dr. I. V. Manzanera Esteve, Prof. E. Y. Chekmenev
Department of Radiology
Vanderbilt University Institute of Imaging Science (VUIIS)
Department of Biomedical Engineering
Vanderbilt-Ingram Cancer Center (VICC)
Vanderbilt University
13
ylates must be developed. Second, %P13C of only 2.3% (using
[13]
on 92% of para-H ) was achieved by Cavallari et al., and
2
a further significant %P13C boost is required for in vivo
applications. Hence, this work is focused on 1) developing an
efficient synthetic procedure for production of vinyl acetate-
Nashville, TN 37232 (USA)
13
1
- C, and 2) investigating the field cycling polarization
Prof. E. Y. Chekmenev
Russian Academy of Sciences
transfer process used in PHIP-SAH to improve %P13C
.
A number of methodologies for the preparation of vinyl
acetate with various isotopic labeling patterns have been
1
19991 Moscow (Russia)
E-mail: eduard.chekmenev@vanderbilt.edu
[17]
described. Roberts et al. developed a procedure based on
Supporting information (all experimental procedures, additional
NMR spectra as well as the schematic description of the hyper-
polarization setup) for this article can be found under
http://dx.doi.org/10.1002/anie.201600521.
14
the mercury-catalyzed reaction of C-labeled acetylene and
acetic acid. Similar methodology, based on stoichiometric
amount of mercury ethoxide and acetyl chloride-D , was
3
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applied to the preparation of vinyl acetate-D by Kim and
3
[
18]
[19]
Caserio. Alternatively, Livshits and Isagulyants showed
14
an efficient reaction between the C-labeled acetic acid and
acetylene catalyzed by zinc acetate in the gas-phase. While
vinyl acetate is industrially produced by vapor-phase acetox-
ylation of ethylene over Pd-based catalysts, such large-scale
gas-phase processes are poorly suited for significantly smaller-
[
20]
13
scale production of isotopically enriched vinyl acetate-1- C.
Earlier variants of synthetic procedures with interexchange of
[
21]
vinyl groups were based on mercury catalysis, which had
some obvious disadvantages of toxicity and laborious workup.
Another potential alternative is based on the recent advances
[22]
in ruthenium-based catalysis.
However, the equilibrium
between vinyl acetate-1- C and its unlabeled counterpart was
not directly amenable to the preparation of vinyl acetate-1-
13
1
3
C.
Replacement of natural abundance vinyl acetate (VA) by
vinyl laurate and the application of distillation column
13
allowed for convenient removal of vinyl acetate-1- C (VA-
1
3
1
- C) from the reaction mixture (Scheme 1a). Owing to the
1
3
Scheme 1. a) Reaction scheme for the preparation of vinyl acetate-1- C
1
3
(
VA-1- C). b) Generalized scheme for preparation of potential targets
1
3
with vinylated C carboxyl groups. The vertical arrows indicate that the
product leaves the mixture as a gas.
1
3
Figure 1. a) Molecular addition of para-H to vinyl acetate-1- C (VA-1-
2
1
3
13
C) followed by polarization transfer resulting in C hyperpolarized
ethyl acetate-1- C ( C HP EA-1- C); b) Conversion profile for vinyl
1
3
13
13
acetate (VA, 80 mm, in [D ]MeOH, at ca. 408C maintained by the 9.4 T
4
flexible nature of the substrates participating in the vinyl
NMR spectrometer) hydrogenation reaction in four pressure regimes;
13
1
exchange, this method of C enrichment can be applied to
a variety of potential PHIP targets, such as pyruvate and
lactate derivatives (Scheme 1b).
c) Dependence of “H ” signal of hyperpolarized ethyl acetate ( H HP
A
EA) on the para-H
bubbling duration at the Earth’s magnetic field
2
[24]
(resulting in ALTADENA -type spectrum shown in inset); d) Top:
schematic representation of the experimental setup for magnetic field
cycling: hydrogenation is carried out at the Earth’s magnetic field, the
sample then is quickly moved inside a m-metal shield (with magnetic
We utilized the Rh catalyst [Rh(NBD)(dppb)]BF4
(
[(bicyclo[2.2.1]hepta-2,5-diene)[1,4-
bis(diphenylphosphino)butane]rhodium(I)
rate) for molecular addition of para-H to VA, analogous to
tetrafluorobo-
field B ) and slowly transferred from the shield for subsequent NMR
FC
2
detection; bottom: schematic magnetic field profile during the field
[12,13]
13
that used in the recent PHIP-SAH studies (Figure 1a).
A
cycling; e) Dependence of HP 1– C NMR signal (shown in the insert)
1
3
13
previously developed setup for high-pressure experiments
of ethyl acetate ( C HP EA) on the BFC; f) Thermal spectrum of
C
1
3
13
[23]
signal reference sodium acetate-1- C (ca. 2.0m); g) C HP spectrum
of natural abundance 80 mm ethyl acetate ( C HP EA). Note the
resonances labeled with 8 correspond to HP C resonances originating
from the hydrogenation catalyst (Figure S7); h) HP C spectrum of
with para-H was utilized (Supporting Information), dem-
2
1
3
onstrating that higher para-H pressure significantly acceler-
2
13
ates VA hydrogenation to EA (Figure 1b). Therefore, the
highest pressure achievable in this setup (ca. 7.2 bar) was used
in further PHIP-SAH experiments. Pairwise addition of 50%
13
13
13
13
8
0 mm ethyl acetate-1- C ( C HP EA-1- C).
para-H was performed in the Earth magnetic field (ca. 50 mT)
2
1
and then the sample was quickly (ca. 2 s) adiabatically
detected HP H NMR signal initially rises (during fast
product build-up) and then decreases (when the contribution
of HP product relaxation overweighs formation of new HP
1
transferred to 9.4 T for HP H NMR detection of nascent
[24]
protons (corresponding to ALTADENA conditions). The
6
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species) with the duration of para-H bubbling (Figure 1c).
The conditions corresponding to bubbling duration of about
approximately 5.5% is clearly largely limited by the HP
source of %P of around 10% in this study and most likely in
recent work by Reineri and co-workers. Therefore, future
studies must focus on the %PH increase and understanding
factors leading to the polarization losses. There are three
2
H
[
13]
8
–10 s yielded maximum observed %P of 3.3% (equivalent
H
1
to H signal enhancement e1H > 1000 fold) and thus, were used
to transfer polarization from HP nascent protons to 1- C
using magnetic field cycling
13
[9,12]
(Figure 1d). In this approach,
possible major %P -reducing barriers: 1) the degree of pair-
H
[5a,26]
the pairwise para-H addition is performed in the Earthꢀs
wise addition of para-H to the vinyl moiety,
2) nascent
2
2
field, the sample is then quickly moved in a magnetic field
protonsꢀ P relaxation, and 3) singlet–triplet mixing of nascent
protons. The first challenge is not a fundamental barrier,
13
[14]
<
1 mT (B ) and hyperpolarization is transferred to
C
FC
during slow (adiabatic) sample transfer back to the Earthꢀs
because similar catalysts yielded %P of around 30–50% on
13C
[14,27]
field (Figures 1c,d). BFC adjustment of polarization transfer
similar molecules
indicating that %P was 50–100%. On
H
13
was carried out by measuring C HP NMR signal of natural
the other hand, the other two barriers have always been
addressed via the use of high-pressure automated spray-
13
abundance EA (ca. 1.1% C in each carbon site) produced by
[8,28]
hydrogenation of 80 mm VA with para-H (Figure 1e). In-
injection PHIP polarizers
operating at elevated temper-
2
shield field (B ) of 0.1–0.2 mT provided the maximal HP
transfer efficiency, and therefore it was used in all subsequent
polarization transfer experiments.
atures, and enabling ultra-fast substrate conversion (1–3 s and
thereby minimizing the effects of spin-lattice relaxation) and
FC
1
H decoupling that allows all molecules to retain the singlet
[14]
The maximum detected e in HP EA was over 2200 fold
states during the course of hydrogenation reaction. While
additional future studies investigating the reasons behind low
1
3C
1
3
for the 1- C site corresponding to %P
of around 1.8%
3C
1
using 50% para-H (Figure 1g). A similar %P
was also
13C
%PH in this and previous PHIP-SAH studies are certainly
2
1
3
13
[8,28]
achieved for HP C EA-1- C (Figure 1h). When compared
warranted, the use of such PHIP polarizers
will likely
13
13
to natural abundance HP EA, HP C EA-1- C carries
around a 90-times greater polarization payload owing to the
provide the remedy and can potentially yield %P of up to
13C
13
50% based on the efficiency of H! C polarization transfer
demonstrated herein. The generality and flexibility of our
trans vinylation approach will benefit future efficient prepa-
ration of other vinylated analogues of metabolically relevant
1
3
13
9
8% C isotopic enrichment of the C site. The enriched site
13
was employed for C 3D ultra-fast magnetic resonance
imaging (MRI; Figure 2) showing the feasibility of high-
[2a,b]
compounds, such as lactate and pyruvate for PHIP-SAH.
This would pave the way for the future in vivo imaging of
[
2a,b]
metabolically impaired conditions such as cancer
and
[
16]
brain damage. In particular, future in vivo studies in animal
models can be carried out with or without Rh-based PHIP
catalysts removal (which are generally well tolerated by
[8a]
[29]
animals and cause no clinical toxicity ) in a manner similar
13
[2e, 8b,10b]
to the previous use of HP succinate-1- C
and HP 2-
The ultimate clinical translation
will require employing Rh-based PHIP catalyst filtration/
removal and improving of the filtration/removal step or the
alternative use of improved heterogeneous PHIP catalysis.
[9,27]
hydroxyethyl propionate.
[8a]
[26]
Moreover, future in vivo translation of this work would
require the use of water-soluble catalysts, which have been
1
3
Figure 2. C 3D MRI of a) a hollow spherical plastic ball partially filled
1
3
with 80 mm HP EA-1- C and b) a plastic sphere (ca. 2.8 mL) filled
successfully employed in combination with high-pressure
1
3
[8,28]
with thermally polarized 4.3m sodium acetate-1- C reference phantom.
Both 3D true-FISP images were acquired using 15 mm outside-
diameter (OD) round radio-frequency (RF) surface coil tuned to
PHIP polarizers
succinate- C,
to produce aqueous solution of HP
13
[10a]
13 [3b]
phospholactate-1- C
and others with
%
P13C exceeding 15% and T in excess of 40 s.
1
1
63.4 MHz in 15.2 T small-animal Bruker MRI scanner (see Supporting
Information for additional details). One representative slice is shown
for each 3D image. SNR=signal to noise ratio.
Acknowledgements
3
resolution (pixel size of 0.5 ” 0.5 ” 4 mm and ca. 2.5 s
This work was supported by NIH 1R21EB018014 and
1R21EB020323, NSF CHE-1416268, DOD CDMRP
W81XWH-12-1-0159/BC112431, and W81XWH-15-1-0271.
We are grateful to Oleg Salnikov for preparing the schematic
description of the hyperpolarization setup in the Supporting
Information.
duration) molecular imaging with this contrast agent using
1
5.2 T Bruker MRI scanner.
If around 100% para-H2
[25]
were to be employed, the
effective %P and %P13C would be tripled to yield 10% and
.5% respectively. These values would more than double the
Moreover, the efficiency of
polarization transfer from nascent para-H protons to 1- C
H
5
[13]
reported pioneering results.
13
Keywords: contrast agents · ethyl acetate · hyperpolarization ·
2
was approximately 50%, which is in quantitative agreement
with previous theoretical simulation for similar spin system of
MRI · para-hydrogen induced polarization (PHIP)
13
[14]
2
-hydroxyethyl propionate-1- C. The expected %P13C of
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Received: January 18, 2016
Revised: February 18, 2016
Published online: April 8, 2016
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