Advances in hardware and molecular design of polarizing agents for dynamic nuclear polarization [Elektronische Ressource] / von Björn Christian Dollmann

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Advances in Hardware andMolecular Design of Polarizing Agents forDynamic Nuclear PolarizationDissertation zur Erlangung des Grades,,Doktor der Naturwissenschaften"im Promotionsfach Physikam Fachbereich Physik, Mathematik und Informatikder Johannes Gutenberg-Universit at in MainzvonBj orn Christian Dollmanngeboren in MainzMainz 2010Dekan:1. Berichterstatter:2. BerichTag der mundlic hen Prufung: 29. November 2010ContentsContents1. Introduction 12. Theoretical Background 32.1. NMR Fundamentals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32.2. EPR Ftals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.3. Dynamic Nuclear Polarization . . . . . . . . . . . . . . . . . . . . . . . . . 203. Technical Aspects of the Mobile Set-up 373.1. Experimental Set-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373.2. Halbach Magnet versus Electromagnet . . . . . . . . . . . . . . . . . . . . 393.3. Shimming of a Halbach Magnet . . . . . . . . . . . . . . . . . . . . . . . . 423.4. DNP Probeheads . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453.5. Implementation of LabVIEW . . . . . . . . . . . . . . . . . . . . . . . . . 494. DNP Performance of the Probeheads 514.1. CUBOID Probehead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514.2. PH1004 Probehead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534.3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Advances in Hardware and
Molecular Design of Polarizing Agents for
Dynamic Nuclear Polarization
Dissertation zur Erlangung des Grades
,,Doktor der Naturwissenschaften"
im Promotionsfach Physik
am Fachbereich Physik, Mathematik und Informatik
der Johannes Gutenberg-Universit at in Mainz
von
Bj orn Christian Dollmann
geboren in Mainz
Mainz 2010Dekan:
1. Berichterstatter:
2. Berich
Tag der mundlic hen Prufung: 29. November 2010Contents
Contents
1. Introduction 1
2. Theoretical Background 3
2.1. NMR Fundamentals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.2. EPR Ftals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.3. Dynamic Nuclear Polarization . . . . . . . . . . . . . . . . . . . . . . . . . 20
3. Technical Aspects of the Mobile Set-up 37
3.1. Experimental Set-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.2. Halbach Magnet versus Electromagnet . . . . . . . . . . . . . . . . . . . . 39
3.3. Shimming of a Halbach Magnet . . . . . . . . . . . . . . . . . . . . . . . . 42
3.4. DNP Probeheads . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3.5. Implementation of LabVIEW . . . . . . . . . . . . . . . . . . . . . . . . . 49
4. DNP Performance of the Probeheads 51
4.1. CUBOID Probehead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
4.2. PH1004 Probehead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
4.3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
5. Overhauser-type DNP Performance of Polarizing Agents 57
5.1. TEMPOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
5.2. Spin-Labeled Heparin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
5.3. Thermoresponsive Spin-Labeled Hydrogel . . . . . . . . . . . . . . . . . . 76
5.4. Summary - Polarizing Agents . . . . . . . . . . . . . . . . . . . . . . . . . 83
6. Solid-State DNP Performance of Polarizing Agents 86
6.1. TEMPOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
6.2. Spin-Labeled Heparin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
6.3. Thermoresponsive Spin-Labeled Hydrogel . . . . . . . . . . . . . . . . . . 104
6.4. Summary - Solid-State DNP . . . . . . . . . . . . . . . . . . . . . . . . . . 106
7. Hyperpolarization of Hetero Nuclei 108
7.1. Hexa uorobenzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
197.2. DNP of a Dissolved F Containing Molecule . . . . . . . . . . . . . . . . 115
137.3. C-Enriched Urea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
i7.4. Summary - Hyperpolarization of Hetero Nuclei . . . . . . . . . . . . . . . 122
8. Conclusion 124
Appendix 128
A. Appendix - Methods 128
A.1. Determination of Unknown Radical Concentrations . . . . . . . . . . . . . 128
A.2. CW EPR Line Shape Analysis . . . . . . . . . . . . . . . . . . . . . . . . 128
A.3. ESE-Detected Line Shape Analysis . . . . . . . . . . . . . . . . . . . . . . 130
A.4. DEER Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
A.5. Electron spin-lattice determination at room temperature . . . . . . . . . . 130
A.6. DNP Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
A.7. Determination of the Quality Factor of the EPR Probeheads . . . . . . . 132
B. Materials - Polarizing Agents, Solvents and Used Molecules 134
B.1. TEMPO Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
B.2. Spin-Labeled Heparin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
B.3. SL-Hydrogel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
B.4. Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
B.5. Solutes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
C. Matlab Scripts 143
C.1. Enhancement and Power Dependence . . . . . . . . . . . . . . . . . . . . 143
C.2. Magnetic Field Sweep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Bibliography 1521. Introduction
1. Introduction
Nuclear magnetic resonance (NMR) is a versatile technique relying on spin-bearing nu-
1,2clei. Since its discovery more than 60 years ago, NMR and related techniques have
become indispensable tools with innumerable applications in physics, chemistry, biology
and medicine. One of the main obstacles in NMR is its notorious lack of sensitivity,
which is due to the minuscule energy splitting caused by the nuclear spins at room tem-
perature. Even for proton spins, which possess the largest magnetogyric ratio, the degree
5of polarization in the highest available magnetic elds (24 T) is only 7 10 . Appro-
priately, the inherent low polarization allows for a theoretical sensitivity enhancement
4of more than 10 . In the eld of magnetic resonance imaging (MRI) this issue becomes
even more severe as the magnetic elds of whole-body tomographs do not reach the eld
strengths of magnets for NMR spectroscopy. Accordingly, MRI is mainly restricted to
13the imaging of water protons and the application of C (or other low nuclei) NMR
spectroscopy and imaging for clinical diagnosis has been constrained by the extremely
long imaging and spectroscopy acquisition times that are required to obtain high signal-
13to-noise ratios under physiological conditions (low natural abundance of C and low
13concentration of C-compounds).
Due to this potential sensitivity increase which can open up completely new research
elds in NMR spectroscopy and imaging, several hyperpolarization techniques have been
developed to overcome this drawback of NMR. The hyperpolarization techniques can be
divided into two sub-groups: (i) Chemistry-based polarization methods like e.g. para-
3{5hydrogen induced polarization (PHIP) and photochemically induced dynamic nuclear
6{8polarization (Photo-CIDNP). (ii) Physics-oriented polarization methods like e.g. op-
9,10 11{15tical pumping of noble gases and dynamic nuclear p (DNP) which was
used in this thesis.
DNP is a polarization technique which transfers the polarization of unpaired electron
spins to the surrounding nuclei by microwave irradiation. The theoretical enhancement
is given by the ratio of the magnetogyric ratios of the electron spin and a nuclear spin.
1 19 13This ratio for proton ( H), uorine ( F) and carbon ( C) nuclei is E 660, E 700
and E 2600, respectively. The most characteristic feature and signi cant drawback
are the presence of unpaired electrons in the sample which have to be added if they are
not inherent to the sample. On the other hand, DNP is not limited to a special molecule
or nucleus which makes it remarkably versatile.
With respect to the possible NMR signal enhancements, especially for low nuclei, many
11. Introduction
new experiments in physics, chemistry, biology and medicine emerge. Particularly in
medicine new diagnostic pathways can be taken by utilizing hyperpolarized substances
13,16as active contrast agent. For example, the metabolism of the physiological rele-
16,17vant substance pyruvate could be examined via MRI. Thus, further development of
technical components and suitable polarizing agents for Overhauser-type and solid-state
DNP are of high importance.
So far, only few medical applications are based on the DNP technique. Nevertheless,
this thesis deals exclusively with the technical development of a mobile DNP polarizer
and the design of suitable polarizing agents for DNP and prospective medical appli-
cations. After this introductory Chapter, the basic theoretical background is given to
comprehend the experimental results of the following parts. The rst part will discuss
the technical improvements which could be achieved regarding the mobile DNP polar-
izer. These improvements comprise the realization of a homogeneous Halbach magnet,
the implementation of an automated experiment control and the construction of new
probeheads. In the Chapters 3 and 4 the importance of these technical improvements
will be demonstrated.
In the main part of this thesis the DNP performance of new polarizing agents is pre-
sented and compared to a commonly used polarizing agent. The DNP performance was
tested at physiological and cryogenic temperatures. Appropriately, Chapter 5 deals with
the Overhauser-type DNP and Chapter 6 with the solid-state DNP. These two Chap-
ters particularly focus on the biocompatibility and removal of polarizing agents which is
an important issue concerning the medical application of hyperpolarized substances via
DNP.
In Chapter 7 the feasibility of DNP experiments on hetero nuclei in the mobile set-up,
working at 0.35 T, is demonstrated. Along with the achieved NMR signal enhancements
by DNP, the measurements prove the possibility of a fast and reliable NMR detection
and nuclear spin-lattice relaxation time determination of biomolecules by using DNP.
This experiment shows the potential of DNP, especially at X-band, when it comes to
the polarization of nuclei with a very low magnetogyric ratio.
22. Theoretical Background
2. Theoretical Background
This Chapter introduces the basic knowledge to understand and interpret the data and
results summarized in the thesis. The presented theoretical fundamentals comprise the
11,12,18topics introduced and explained in many publications, books and reviews. The
Chapter can be divided into four parts. First, the basic principles of nuclear magnetic
resonance (NMR) are explained and its limitations are discussed. Next, the most im-
portant properties of the similar method electron paramagnetic resonance (EPR) and
its advantages and disadvantages as compared to NMR are presented. In Section 2.3 the
basics of dynamic nuclear polarization (DNP) are described in the context of the bene ts
of combining NMR and EPR and its use for new and powerful applications, especially
in the wide eld of medicine. The last part concludes with the used theoretical tools for
the shimming of a Halbach magnet by utilizing permanent magnets.
2.1. NMR Fundamentals
NMR and magnetic resonance in general rely on the inherent quantum mechanical prop-
erty of elementary particles: the spin. Spin-bearing particles possess a non-zero spin
angular momentum which is an intrinsic property, like the mass, of the particle. Neu-
trons and protons which are the constituents of nuclei carry the spin-quantum number
1=2. Therefore, the resulting spin-quantum number of a nucleus can be either integer or
half-integer. Its characteristic magnetic moment for a non-zero spin-quantum numberI
is collinear to its momentum and de ned by
= ~I ; (2.1)I I
where denotes the magnetogyric ratio of the nucleus and~ =h=2 is Planck’s constantI
divided by 2. The time evolution of observables in quantum mechanics (QM) obeys
the time-dependent Schr odinger Equation 2.2:
@
^i~ j(t)i =Hj(t)i ; (2.2)
@t
^wherej(t)i is the state of the spin system at time t andH is the Hamilton-operator
32. Theoretical Background
(Hamiltonian). The spin Hamiltonian of a nuclear system at a magnetic eld reads as
^ ^ ^ ^ ^ ^H =Z +H +H +H +H : (2.3)I rf cs II Q
^In 2.3Z is the nuclear Zeeman interaction with the externally applied magnetic eldI
^andH represents the interaction of the nuclear spins with the radio-frequency (rf)rf
^ eld. H denotes the in due to chemical shift. This term is omitted as thecs
spectral resolution and its analysis are of minor interest for the purpose of the thesis.
The last two terms represent the mutual interactions due to dipolar and quadrupolar
interactions, respectively. Quadrupolar in emerge only for nuclear spins with
1 13I > 1=2. As this work exclusively deals with I = 1=2 nuclei ( H and C), it is not
further considered here. Furthermore, as for DNP all samples are doped with radicals
(unpaired electrons), the nuclear spin-nuclear spin interactions are at least one order
18,19of magnitude smaller than electron spin-nuclear spin interactions. Therefore, the
only remaining interactions are of external kind and will be discussed in the following
Subsections.
External Nuclear Spin Interactions
^Z in Equation 2.3 is the interaction energy of the nuclear spin momentum with theI
applied external magnetic eld B :0
^E =Z = B = ~IB : (2.4)I I I 00
If the external magnetic eld B is aligned along the z-axis in the laboratory frame,0
TB = (0; 0;B ) , the energy levels depend only on the magnetic spin-quantum number0 0
m:
E = m~B : (2.5)m I 0
The magnetic spin-quantum numberm can only acquire the valuesjmjI. Every state
with the spin-quantum numberm can occupy 2m + 1 sub-levels which are degenerate in
the absence of an external magnetic eld. The energy di erence between these sub-levels
scales linearly with the applied magnetic eld:
E =E E = ~B = ~! ; (2.6)m+1 m I 0 0
4