University of Groningen
Modular Approaches in PET-tracer Development Böhmer, Verena
DOI:
10.33612/diss.133809999
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Publication date: 2020
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Böhmer, V. (2020). Modular Approaches in PET-tracer Development: Radiotracer Design, Synthesis and Automation for Prostate Cancer and Heart Failure. University of Groningen.
https://doi.org/10.33612/diss.133809999
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ModularApproaches in PET-tracer
Development
Radiotracer Design, Synthesis and Automation
for Prostate Cancer and Heart Failure
The research described in this dissertation was carried out at the Department of Nuclear Medicine and Molecular Imaging at the University Medical Center Groningen and the Stratingth Institute of Chemistry of the University of Groningen, The Netherlands. The project was coordinated within the the research school of Cancer Research Centrum Groningen.
This work was financally supported by the provinces Overijssel and Gelderland, as being part of the PET/MRI project of the Center for Medical Imaging North East Netherland. This work was conducted in collaborations with Syncom BV, FutureChemistry and Comecer.
Printing of this thesis was supported by the University of Groningen, Graduate School for Medical Sciences and the University Medical Center Groningen.
Cover Design and Thesis Layout: Verena Ivonne Böhmer Print: Ridderprint BV, The Netherlands
Modular Approaches in PET-tracer Development
Radiotracer Design, Synthesis and Automation for Prostate Cancer and Heart Failure
Proefschrift
Ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op woensdag 30 september 2020 om 16.15 uur.
door
Verena Ivonne Böhmer
geboren op 28 september 1990 te Münster, Duitsland
Promotores
Prof. dr. P. H. Elsinga Prof. dr. B. L. Feringa Prof. dr. W. Szymanski
Beoordelingscommissie
Prof. dr. M. Hendriks – de Jong Prof. dr. ir. A. J. Minnaard Prof. dr. K. Kopka
vii
TABLE OF CONTENTS
CHAPTER 1
INTRODUCTION ... 1
1.1MODULARITY ... 2 1.2MEDICAL IMAGING ... 21.2.1 Positron Emission Tomography ... 2
1.2.2 Radiotracer ... 4
1.3DISEASE-SPECIFIC TARGETING OF RADIOTRACER ... 5
1.3.1 Prostate cancer ... 5
1.3.2 Heart failure ... 7
1.4MODULARITY IN RADIOTRACER METHODOLOGY ... 8
1.4.1 Click chemistry ... 8
1.4.2 The Mechanism of CuAAC ... 10
1.5OUTLINE OF THE THESIS ... 12
1.6REFERENCES ... 13
CHAPTER 2
MULTIVALENT PROBES IN MOLECULAR IMAGING: REALITY OR
FUTURE?... 19
2.1INTRODUCTION ... 21
2.1.1 Molecular imaging ... 21
2.1.2 Molecular imaging agents ... 21
2.1.3 Achieving high binding affinity ... 22
2.1.4 Multivalency increases the binding potential ... 22
2.2THERMODYNAMICS OF MULTIVALENT BINDING ... 23
2.3PHARMACODYNAMICS OF MULTIVALENT CONSTRUCTS ... 24
2.3.1 Design aspects for MMIAs ... 25
2.4PHARMACOKINETICS AND BINDING POTENTIAL ... 27
2.4.1 The fate of molecular imaging agents on their journey throughout the body .... 28
2.5OTHER FACTORS INFLUENCING THE BINDING POTENTIAL OF MMIAS ... 29
2.5.1 Chameleon behavior of MMIAs ... 29
2.5.2 Solubility effects influence tissue uptake of MMIAs ... 30
2.5.3 Preparation of MMIAs and quantification of ligand density ... 30
2.5.4 Biodegradation of MMIAs ... 30
2.6TRANSLATION TO THE CLINICS ... 31
2.7STEPWISE APPROACH TO DESIGN MULTIVALENT MOLECULAR IMAGING AGENTS ... 33
2.8CONCLUDING REMARKS ... 35
2.9REFERENCES ... 36
CHAPTER 3
TOWARDS MODULAR MEDICAL IMAGING AGENTS: SYNTHESIS
AND
PRE-CLINICAL EVALUATION OF [
18F]PSMA-MIC01 ... 41
3.1INTRODUCTION ... 43
3.2RESULTS AND DISCUSSION ... 45
3.2.1 Design of F-PSMA-MIC01 ... 45
viii
3.2.3 Radiolabeling of [18F]PSMA-MIC01 ... 47
3.2.4 In vitro studies of F-PSMA-MIC01 ... 48
3.2.5 In vivo studies of [18F]PSMA-MIC01 ... 49
3.3CONCLUSIONS ... 52 3.4ACKNOWLEDGEMENT ... 52 3.5EXPERIMENTAL SECTION ... 52 3.5.1 General Materials ... 52 3.5.2 Organic Chemistry ... 53 3.5.3 Radiochemistry ... 56 3.5.4 Cell culture ... 59 3.5.5 Animal study ... 60 3.6REFERENCES ... 61
CHAPTER 4
18F-FLUORINATIONS AND AUTOMATED CLICK CHEMISTRY
USING MICROFLUIDICS ... 65
4.1INTRODUCTION ... 67
4.2RESULTS AND DISCUSSION ... 69
4.2.1 Design ... 69
4.2.2 Set-up ... 70
4.2.3 Improving of the set-up by implementation of [18F]PSMA-MIC01 ... 73 4.2.4 Implementation of five different 18F-fluorinations on the FlowSafe radiosynthesizer module ... ...75 4.2.4.1 Radiosynthesis of [18F]PSMA-MIC02 ... 76 4.2.4.2 Radiosynthesis of [18F]fluoro-pyridine ... 76 4.2.4.3 Radiosynthesis of [18F]SFB ... 77 4.2.4.4 Radiosynthesis of [18F]PSMA-1007 ... 78 4.3CONCLUSIONS ... 81 4.4ACKNOWLEDGEMENT ... 81 4.5EXPERIMENTAL SECTION ... 81 4.5.1 General Materials ... 81 4.5.2 Radiochemistry ... 81 4.6REFERENCES ... 84
CHAPTER 5
SECONG GENERATION OF F-PSMA-MIC: IMPROVING BINDING
AFFINITY BY TARGETING THE ARENE-BINDING SITE OF PSMA
... 87
5.1INTRODUCTION ... 89
5.2RESULTS AND DISCUSSION ... 90 5.2.1 Design of 2nd generation F-PSMA-MIC compounds ... 90 5.2.2 Synthesis of precursors and F-PSMA-MIC01 ... 91
5.2.3 Molecular modeling studies of F-PSMA-MIC compound ... 91 5.2.4 In vitro studies of the 2nd generation F-PSMA-MIC compound ... 93 5.2.5 Radiolabeling of the end generation radiotracer [18F]PSMA-MIC02 ... 94
5.3CONCLUSIONS ... 95
5.4ACKNOWLEDGEMENT ... 95 5.5EXPERIMENTAL SECTION ... ..95
ix 5.5.2 Organic Chemistry ... .96 5.5.3 Radiochemistry ... 105 5.5.4 Cell culture ... 108 5.5.5 Computational Details ... 108 5.6REFERENCES ... 113
CHAPTER 6
THE EFFECT OF MULTIVALENCY ON BETA-ADRENERGIC
RECEPTOR LIGANDS ... 117
6.1INTRODUCTION ... 119
6.2RESULTS AND DISCUSSION ... 121
6.2.1 Design of β-blocker series ...121 6.2.2 Synthesis ... 122 6.2.3 In vitro studies ... 123 6.2.4 Consensus molecular docking ... 124 6.3CONCLUSIONS ... 127 6.4ACKNOWLEDGEMENT ... 127 6.5EXPERIMENTAL SECTION ... 127 6.5.1 General Materials ... 127 6.5.2 Organic Chemistry ... 128 6.5.3 Cell culture ... 130 6.5.4 Molecular docking studies ... 131 6.5.4.1 Consensus docking poses ... 132 6.6REFERENCES ... 135
CHAPTER 7
DISCUSSION, FUTURE PERSPECTIVE AND CONCLUSION ... 139
7.1DISCUSSION ... 140 7.2FUTURE PERSPECTIVE ... 142 7.3CONCLUSION ... 147 7.4REFERENCES ... 147
