Preclinical evaluation of somatostatin analogues for breast cancer imaging using positron emission tomography.
department or school: Medicine, Faculty of
data provider: DSpace
degree campus: UBCV
creator: Dude, Iulia Gabriela
issued: 2017-09-30T00:00:00
issued: 2017
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Somatostatin receptors (sstrs) are G-protein coupled receptors that modulate hormone secretions. Their overexpression on neuroendocrine tumours (NETs) has enabled successful imaging of these cancers with radioactive peptides using positron emission tomography. Luminal A breast cancers also overexpress sstr, but with a lower and more heterogeneous density than NETs. Recently, several authors demonstrated higher tumour binding with sstr antagonists compared to agonists. Antagonists are hypothesized to bind to target receptors in multiple configurations, thus labeling more binding sites than high-affinity agonists. This property could result in better visualization of tumours with lower sstr density, such as breast cancers. We hypothesized that the somatostatin agonist peptides TOC and TATE and antagonist peptide JR11 could be radiolabeled with ⁶⁸Ga and ¹⁸F, and that antagonist radiotracers will show higher tumour uptake when evaluated in vivo using the human breast cancer xenograft ZR-75-1. We synthesized the literature compounds ⁶⁸Ga-DOTATOC, ⁶⁸Ga-DOTATATE and antagonist ⁶⁸Ga-NODAGA-JR11 and evaluated binding affinity and tumour uptake. The agonist ⁶⁸Ga-DOTATOC had the highest tumour uptake (18.4 ± 2.87 %ID/g), and the antagonist ⁶⁸Ga-NODAGA-JR11, the lowest (12.1 ± 0.78 %ID/g). We radiolabeled the same peptide analogues with ¹⁸F using the easy and robust AmBF₃ method. ¹⁸F is an excellent isotope for peptide radiolabeling, having low positron energy (634 keV), a half-life well-matched to peptide kinetics (110 min), and an established cyclotron production method. We synthesized the compounds ¹⁸F-AmBF₃-TOC, ¹⁸F-AmBF3-TATE and ¹⁸F-AmBF3-JR11 and found that all were kinetically stable (determined by in vivo plasma stability studies) and successfully visualized the tumour with high intensity and contrast at both 1 hour and 2 hours post-injection (p.i.). At 1 h p.i. uptake means were between 10.0 – 13.4 %ID/g for all three radiotracers, and differences were not statistical…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/61078
note: PRECLINICAL EVALUATION OF SOMATOSTATIN ANALOGUES FOR BREAST CANCER IMAGING USING POSITRON EMISSION TOMOGRAPHY by Iulia Gabriela Dude B.Sc., The University of Waterloo, 2014 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Interdisciplinary Oncology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) March 2017 © Iulia Gabriela Dude, 2017 ii Abstract Somatostatin receptors (sstrs) are G-protein coupled receptors that modulate hormone secretions. Their overexpression on neuroendocrine tumours (NETs) has enabled successful imaging of these cancers with radioactive peptides using positron emission tomography. Luminal A breast cancers also overexpress sstr, but with a lower and more heterogeneous density than NETs. Recently, several authors demonstrated higher tumour binding with sstr antagonists compared to agonists. Antagonists are hypothesized to bind to target receptors in multiple configurations, thus labeling more binding sites than high-affinity agonists. This property could result in better visualization of tumours with lower sstr density, such as breast cancers. We hypothesized that the somatostatin agonist peptides TOC and TATE and antagonist peptide JR11 could be radiolabeled with 68Ga and 18F, and that antagonist radiotracers will show higher tumour uptake when evaluated in vivo using the human breast cancer xenograft ZR-75-1. We synthesized the literature compounds 68Ga-DOTATOC, 68Ga-DOTATATE and antagonist 68Ga-NODAGA-JR11 and evaluated binding affinity and tumour uptake. The agonist 68Ga-DOTATOC had the highest tumour uptake (18.4 ± 2.87 %ID/g), and the antagonist 68Ga-NODAGA-JR11, the lowest (12.1 ± 0.78 %ID/g). We radiolabeled the same peptide analogues with 18F using the easy and robust AmBF3 method. 18F is an excellent isotope for peptide radiolabeling, having low positron energy (634 keV), a half-life well-matched to peptide kinetics (110 min), and an est…
has type: Thesis/Dissertation
date issued: 2017-05
is shown at: 10.14288/1.0343426
language: eng
degree discipline: Interdisciplinary Oncology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/61078