Development of magnetic resonance guided functional and anatomical markers for the brain [Elektronische Ressource] = Entwicklung von Markierungssubstanzen für die funktionelle und anatomische Kernspinresonanztomografie des Gehirns / vorgelegt von Kirti Dhingra

Kirti

Informations

• Publié par: eberhard_karls_universitat_tubingen
• Publié le: 01 janvier 2009
• Nombre de lectures: 12
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

Development of Magnetic Resonance Guided Functional and
Anatomical Markers for the Brain

Entwicklung von Markierungssubstanzen für die funktionelle und
anatomische Kernspinresonanztomografie des Gehirns


DISSERTATION
der Fakultät für Chemie und Pharmazie
der Eberhard-Karls-Universität Tübingen

zur Erlangung des Grades eines Doktors
der Naturwissenschaften


2009
vorgelegt von
Kirti Dhingra


















Tag der mündlichen Prüfung: 4. Februar 2009
Dekan: Prof. Dr. Lars Wesemann
1. Berichterstatter: Prof. Dr. Martin E. Maier
2. Berichterstatter: Dr. Karl-Heinz Wiesmüller
2 
 This doctoral thesis was carried out at the Dept. of Physiology of Cognitive Processes of the Max
Planck Institute for Biological Cybernetics under the supervision of Prof. Dr. Nikos K.
Logothetis and in collaboration with the Institute for Organic Chemistry, Eberhard-Karls-
University, Tübingen under the guidance of Prof. Dr. Martin E. Maier during the period from
September 2004 to January 2009.















I would like to thank Max Planck Society and Hertie Foundation for the financial support to
carry out this work
Tübingen, Januar 2009
3 
 Acknowledgement
I would like to express my heartfelt gratitude to all who gave me possibilities to complete this
thesis.
I would like to thank Prof. Nikos K. Logothetis who gave me an opportunity to pursue my Ph.D
in his esteemed research group. His constant support, encouragment and trust kept me moving
with great enthusiasm through out my doctoral work. He gave me the confidence and freedom to
expand my theories and ideas.
I would like to thank Prof. Martin E. Maier who constantly supervised my work. His
suggestions, ideas, and valuable comments significantly helped me understanding the chemistry
in various facets.
I am very thankful to Prof. Karl-Heinz Wiesmüller for reviewing my doctoral thesis and giving
valuable comments.
My sincere thanks go to Dr. Santiago Canals and Dr. Joern Engelmann for all the helpful
discussions on the problems I faced during my research work.
I express my special thanks to Dipl. –Ing. Michael Beyerlein. Without his help in performing the
measurements in the University of Tuebingen and in Max Planck Institute, I would not have been
able to finish this thesis in time.
I am thankful to Prof. Almut Schüz for doing the histology experiments and Dr. Rolf Pohmann
for performing the MR experiments at different magnetic field.
I owe a sincere thanks to Prof. Anil K. Mishra who guided me in the beginning of my research
career and showed me the right way to realize my research ambitions I also thank Dr. Éva Jakab Tóth and Dr. Petra Fousková, Centre de Biophysique Moléculaire,
CNRS, France for performing the physicochemical characterization of the synthesized agents
and helped me in learning the project from an inorganic chemist point of view.
I thank Dr. Klaus Eichele, Dr. Caecilia Maichle-Moessmer and Ms. Elke Niquet for doing the X-
ray crystallography. I would also thank Graeme Nicholson for doing the high resolution MS.
I would like to thank Dr. Goran Angelovski, Dr. Jozien Goense, and Dr. Anurag Mishra for
reviewing my thesis and giving the useful comments. I thank all the members of bioconjugate
chemistry group: Dr. Anurag Mishra, Dr. Ilgar Mamedov, Dr. Goran Angelovski, Dr. Jörn
Engelmann, Dr. Rajendra Joshi, Aneta Brud, Deepti Jha, Ritu Mishra, and Hildegard Schülz for
creating a good working atmosphere.
I am very thankful to Aneta Brud, Vishal Kapoor, Vishnudev, Vikram, Anurag Mishra, Ritu
Mishra, and Deepti Jha. Their help, optimism, and energy made my stay in Tuebingen cheerful.
Finally I would like to thank my dear brother, Ashwini. Without his constant support and care
throughout my education, I would not have been able to explore this part of the world outside my
home country, India. I would also thank my sis-in-law and my sisters for their support and
optimism.
I would pay tribute to my parents who taught me that hard work is the key to success. I thank
them for nurturing and educating me. Thank you is not sufficient but it is said with great
appreciation and respect.




5 
 Abbreviations
Abbreviations
ACSF Artificial cerebrospinal fluid
AECM extracellular matrix
APTRA o-aminophenol-N,N,O-triacetate
Boc tert-Butoxy carbonyl
BOLD Blood oxygenation level dependent
BAPTA 1,2-bis(o-aminophenoxy)ethane-N,N,N’,N’-
teteracetic acid
tert-Bu tert-butyl
Cbz Chlorobenzoformate
CDCl Chloroform-deuterated 3
CEST Chemical exchange saturation transfer
CLIO Cross linked nanoparticle
DMF Dimethyl formaide
DCC Dicyclohexylcarbodiimide
DO Deuteriumoxide 2
DTPA Diethylenetriaminepentaacetic acid
EDTA ethylenediaminetetracetic acid
ECM Extracellular matrix
DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic
acid
DO3A 1,4,7,10-tetraazacyclododecane-1,4,7-tetracetic
acid Abbreviations
 
DMAP 4-Dimethylaminopyridine
DIEA Diisopropylethylamine
ECM Extracellular matrix
EDC 1-Ethyl-3-(3’-dimethylaminopropyl)carbodiimide
ESI-MS Electron Spray Ionization – Mass Spectrometry
equiv Equivalents
eq Equation
FT Fourie Transform
h Hour (s)
Hz ertz
HATU 2-(1H-7-Azabenzotriazol-1-yl)--1,1,3,3-tetramethyl
uronium hexafluorophosphate Methanaminium
HOBt Hydroxybenzotriazole
HPLC High performance liquid chromatography
ICP-OES Inductively Coupled Plasma Optical Emission
Spectrometry
i-Bu Isobutyl
J Coupling constant
Ln Lanthanide
LiOH Lithium hydroxide
MeCN Acetonitrile
MeOD-d4 Methanol-deuterated
m/z Mass to charge ratio
7 
 Abbreviations
 
mmol millimole
mM Milmolar
mAb monoclonal antibody
MRI Magnetic resonance imaging
fMRI Functional magnetic resonance imaging
NMP N-methylpyrolidinone
NMRD Nuclear magnetic resonance dispersion
NMM methylmorpholine
Pd-C Palladium on activated carbon
PyBrop Bromo-trispyrrolidino-phosphonium
hexafluorophosphate
R Retention factor f
RT Rom teperature
RM Reaction mixture
RIME Receptor induced magentisation enhancement
RP-HPLC Reversed phase high performance liquid
chromatography
SPIO superparamagnetic iron oxide
TBAF Tetrabutylammoniumfluoride
TBDMS Tert-Butyldimethylsilylether
TFA Trifluoroacetic acid
THF Tetrahydrofuran

8 
 Table of Contents
Table of Contents 
A. Section A: Introduction
CHAPTER 1 .............................................................................................................................................. 14
1. MAGNETIC RESONANCE IMAGING ............................................................................................ 14
1.1 Basic principle ................................................................................................................................. 14
1.2 Relaxation times ............................................................................................................................. 16
1.3 Measuring relaxation times and constructing an image in MRI ................................................ 17
1.3.1 Pulse sequences ... 17
1.3.2 Magnetic field gradients .............................................................................................. 18
1.4 Contrast in MR images ................................................................................................................... 21
CHAPTER 2 .............................................................................................................................................. 22
2. MRI and Contrast agents ..................................................................................................................... 22
2.1 Introduction ..................................................................................................................................... 22
2.2. Contrast agents in action: Mechanism and Theory .................................................................... 23
2.2.1 Paramagnetic agents 23
2.2.2 Superparamagnetic agents ........................................................................................... 25
2.2.3 CEST agents ................................................................................................................. 28
2.3. Contrast agents and their applications ........................................................................................ 29
2.3.1 Compartmental probes ................................................................................................. 29
2.3.2 Targeted Pro