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Molecular Imaging of Breast Cancer MOLECULAR IMAGING OF BREAST CANCER USING PARACEST MRI by BYUNGHEE YOO Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Thesis Advisor: Prof. Mark D. Pagel, Ph.D. Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY August, 2007 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ________________BYUNGHEE YOO_____________________ candidate for the Doctor of Philosophy degree *. (signed) Mark D. Pagel, Ph.D. (chair of the committee) Raymon F. Muzic, Ph.D. Suneel S. Apte, Ph.D. Xin Yu, Sc.D. (date) June 15, 2007 *We also certify that written approval has been obtained for any proprietary material contained therein. Copyright © 2006 by Byunghee Yoo All rights reserved iii DEDICATION To my family and my mentors iv Table of Contents Title page …..……………………………………………………………..…………. …. i Committee signature …………..…………………………………………..………... …. ii Copyright……………………………………………………………………………. … iii Dedication ………………………………………………………………………..…. ….iv Table of Contents..………………………………………………………….….……. …..1 List of Tables..……………………………………………………………….…...…. …..4 List of Schemes…………………………………………………………….….….…. …..5 List of Figures……………………………………………………………….….….... …..6 Preface……………………………………………………………………….….….... …..8 Acknowledgements……………………………………………………..….………... .…10 List of Abbreviations…………………………………………………………………….12 Abstract……………………………………………………………….……………... .....13 Chapter I. Introduction………………………………………………………………… ..15 1. Breast cancer and molecular MR imaging……………………………………. ..16 A. Breast cancer and biomarkers……………………………………………... ..16 B. Detection of biomarkers in breast cancer………………………...……….. ..18 2. MRI and MR contrast…………………………………………………………. ..21 A. General concept of MRI………………………………...………………… ..21 B. T1, T2 relaxation times and contrast……………………………...……….. ..24 C. Paramagnetic Chemical Saturation Transfer (PARACEST) ……...……… ..30 3. References…………………………………………………………………….. ..35 Chapter II. Responsive MR contrast agents…………………………………………… ..41 1. Introduction……………………………………………………………………...42 2. Exogenous MR contrast agents……………………………………………….....42 3. Responsive MR contrast agents……………………………………………….. ..47 A. Responsive MRI contrast agents for molecular imaging of proteins……... ..47 a. Contrast agents that bind to proteins…………………………………. ..47 b. Contrast agents that are catalyzed by enzymes……………….......... ….49 B. Responsive MRI contrast agents for molecular imaging of nucleic acids... ..51 C. Responsive MRI contrast agents for molecular imaging of metabolites…. ..53 D. Responsive MRI contrast agents for molecular imaging of oxygen……… ..54 E. Responsive MRI contrast agents for molecular imaging of metal ions…......55 1 F. Responsive MRI contrast agents for molecular imaging of pH…………... ..57 G. Responsive MRI contrast agents for molecular imaging of temperature…. ..61 4. Future directions………………………………………………………………. ..62 5. References…………………………………………………………………….....66 Chapter III. Solution phase synthesis of molecular imaging contrast agents………........75 1. Introduction……………………………………………………………………...76 2. Experimental methods………………………………………………………… ..78 A. General methods…………………..………………………………………...78 B. Synthesis and characterization…………..………………………………... ..79 3. Results and discussions……………………………………………………….....87 4. Conclusions……………………………………………………………………...91 5. References…………………………………………………………………….....92 Chapter IV. Solid phase synthesis of molecular imaging contrast agents………….......101 1. Introduction…………………………………………………………………… 102 2. Experimental methods………………………………………………………… 105 A. General methods………………………………………….……..………… 105 B. Synthesis and characterization……………………………...…………….. 107 3. Results and discussions……………………………………………………….. 117 4. Conclusions…………………………………………………………………… 132 5. References…………………………………………………………………….. 134 Chapter V. Detection of enzyme activity using the PARACEST effect………………. 154 1. Introduction…………………………………………………………………… 155 2. Experimental methods………………………………………………………… 159 3. Results and discussions……………………………………………………….. 166 4. Conclusions…………………………………………………………………… 183 5. References…………………………………………………………………….. 185 Chapter VI. Contrast agents for DCE-MRI…………………………………………… 189 1. Angiogenesis and microvasculature…………………………………………... 189 2. Dynamic contrast-enhnaced magnetic resonance imaging (DCE-MRI)……… 191 A. Arterial input function (AIF)………………………………………..….…. 192 B. Contrast agents…………………………………………………..………... 194 a. Small molecular contrast agent (SMCA)…………………………….. 196 2 b. Intermediate molecular contrast agent (IMCA)……………………… 196 c. Large molecular contrast agent (LMCA)…………………………….. 198 3. Summary ………………………………………………………………………. 204 4. References…………………………………………………………………….. 206 Chapter VII. PARACEST DCE-MRI………………………………………………….. 218 1. Introduction…………………………………………………………………… 219 2. Experimental methods………………………………………………………… 220 A. Synthesis of molecular imaging probes………………...………………… 220 B. Cell culture and flank tumor model……………………..………………... 224 C. PARACEST DCE-MRI………………………………..…………………. 224 D. Analysis of DCE-MRI data…………………………...…………………... 227 3. Results………………………………………………………………………… 235 A. Contrast agents………………………………………….……..………….. 235 B. Tumor model and catheterization………………………...……………….. 238 C. T1 DCE-MRI……………………………………………………………… 240 D. PARACEST DCE-MRI…………………………………...………………. 241 4. Discussion……………………………………………………………………... 247 5. References…………………………………………………………………….. 251 Chapter VIII. Future research…………………………………………………………. 254 1. Development of contrast agents………………………………………………. 256 A. Synthesis of DOTA derivatives…………………………..………………. 256 B. Polymeric / dendrimeric templates………………………..……………… 265 2. Applications for diagnostic/clinical research…………………………………. 266 3. Detection of endopeptidase activity…………………………………………... 269 Appendix……………………………………………………………………………….276 A1. Michaelis-Menten kinetics versus CEST concentration calibration…..……… 276 A2. MEROPS database……………………………………………………………. 282 3 List of Tables Table 2.1 Structures of responsive MR contrast agents………………….……………..72 Table 4.1 The amine contents on the resin measured by picric acid titration….……… 113 Table 5.1 Michaelis-Menten kinetics parameters……………………………….…….. 177 Table 5.2 Stratification of human proteases by catalytic mechanism………….……… 182 Table 6.1 Examples of blood pool agents (BPAs) in DCE-MRI……………….…....... 195 Table 7.1 The loading amounts of each contrast agents.……………………….……… 226 Table 7.2 Three standard kinetic parameters in DCE-MRI………………….………… 230 Table 7.3 Working quantities in DCE-MRI………………………………….………... 231 Table 7.4 Relaxivities of contrast agents for DCE-MRI experiments……….………... 235 Trans Table 7.5 Summary of K from T1 and PARACEST DCE-MRI……….…………... 242 Table 8.1 MMP’s substrate peptide sequences…………………..………….………… 275 Table A1.1 A comparison of graphical analysis methods to evaluate Michaelis-Menten kinetics parameters………………………………………………………... 278 Table A2.1 Human peptidases…………………………………………….…………… 284 4 List of Schemes Scheme 3.1 Synthesis of α-brominated glycine templates……….…...………………. .95 Scheme 3.2 Synthesis of α-amino-DOTA derivatives and coupling to a peptide backbone carboxylate group………………………………………………. .96 Scheme 4.1 Preparation of amino-DOTA pre-loaded polymeric support….…….….....141 Scheme 4.2 Synthesis of peptidyl contrast agents……………………….…………….142 Scheme 7.1 Synthesis of DOTAMGly…………………………………………………253 Scheme 8.1 Tentative synthetic pathway of Fmoc-Gly(DOTA-tBu)-OH…….……...... 259 Scheme 8.2 Proposed mechanism of enzyme responsive peptidyl phosphate DOTA.... 260 Scheme 8.3 Tentative synthetic scheme of peptidyl phosphate DOTA with doxorubicin.…………………………………………………………. 261 Scheme 8.4 Tentative enzyme responsive MR contrast agent based on trimethyl lock mechanism………………………………………………………………… 262 Scheme 8.5 Tentative synthetic pathway of Fmoc-Gly(DOTA-tBu) derivative for ligation…………………………………………………………………….. 263 Scheme 8.6 Tentative synthetic pathway of Fmoc-AA(DOTA-tBu)-OH…….……...... 264 5 List of Figures Figure 1.1 The tipping and relaxation of magnetization Mo relative to Bo…………… .23 Figure 1.2 Schematic of the interactions of water molecules with a lanthanide (III)-based contrast agent………………………………. .29 Figure 1.3 Chemical structures of DOTA, DOTAM and DOTAMGly………………... .32 Figure 1.4 Schematics for the mechanism of PARACEST effects……………………. .33 Figure 3.1 1H-NMR spectrum of Cbz-Gly(OH)-OH………………………………….. .97 Figure 3.2 1H-NMR spectrum of Cbz-Gly(OMe)-OMe……………………………..... .97 Figure 3.3 1H-NMR spectrum of Cbz-Gly(Br)-OMe………………………………...... .98 Figure 3.4 1H-NMR spectrum of Boc-Gly(Br)-tBu…………………………………… .98 Figure 3.5 1H-NMR spectrum of Boc-Gly-tBu-DO3A-tBu (Boc-amino-DOTA)…...... .99 Figure 3.6 1H-NMR spectrum of Cbz-Gly-OMe-DO3A-tBu (Cbz-amino-DOTA).…... .99 Figure 3.7 1H-NMR spectrum of amino-DOTA……………………………………..... 100 Figure 3.8 Maldi-Mass Spectral analysis of Ac-PLGMWSG-amino-DOTA…………. 100 Figure 4.1 Ninhydrin color test to qualitatively analyze the amine content on the resin………………………………………………………………... 113 Figure 4.2 The amine content following CBZ cleavage versus reaction time ....... 143 Figure 4.3 Two possible transition states of Et2AlCl and CBZ-aminoDOTA Wang resin………………………………………………………………… 144 Figure 4.4 The PARACEST spectra…………………………………………………… 145 Figure 4.5 The proximity of amide hydrogens to Tm3+……………………………….. 146 Figure 4.6 Dependencies of the PARACEST effects on environmental conditions…... 147 Figure 4.7 The calibration of the PARACEST effect relative to concentration……….. 148 Figure 4.8 1H-NMR Spectrum of Cbz-Gly(OH)-OH…………………………………. 149 Figure 4.9 1H-NMR
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