Evaluation of novel positron emission tomography radiotracers in humans: tissue distribution kinetics and potential for cancer diagnosis and staging
File(s)
Author(s)
Dubash, Suraiya Rahim
Type
Thesis
Abstract
Positron emission tomography (PET) imaging has emerged as an important decision-making
tool in oncology with respect to diagnosis, staging, and assessment of treatment response. We
proposed to investigate the ligand binding and retention kinetics of two novel PET/CT tracers
in human tumours that do not normally exhibit high [18F]fluorodeoxyglucose ([18F]FDG)
uptake, and a third tracer in the context of specific death mechanism. Biological validation of
the imaging endpoint included histological correlation with PET/CT data and establishment of
an optimum PET/CT methodologies for the probe for implementation into clinical practice.
The internal dosimetry and receptor-mediated tumour localisation of the ‘click’ labelled
[18F]fluoroethyl triazole octreotate analogue, [18F]FET-βAG-TOCA, in neuroendocrine
tumours (NETs) were investigated for the first time in humans. The biomarker demonstrated
favourable dosimetry, biodistribution and safety. The calculated effective dose over all subjects
(mean ± SD) was 0.029 ± 0.004 mSv/MBq. Regarding staging, [18F]FET-βAG-TOCA PET/CT
showed high tumoural uptake with high sensitivity (per lesion) compared with
[68Ga]DOTATATE PET/CT (92.8% vs 87.5%).
Tissue retention kinetics of the novel choline analogue, [18F]fluoromethyl-[1,2-2H4]-
choline ([18F]D4-FCH) were investigated in the staging of muscle invasive bladder cancer
(MIBC) and non-small cell lung cancer (NSCLC). The biomarker showed high contrast in lung
cancer but poor contrast in bladder cancer. In lung tumours, [18F]D4-FCH uptake was
quantitatively lower than [18F]FDG. Pharmacokinetic modelling revealed net tracer influx in
tumour consistent with radiotracer phosphorylation via choline kinase, however choline
kinase-alpha expression did not correlate with PET parameters.
Beyond staging, we evaluated for the first time a caspase-3/7 imaging biomarker, [18F](S)-
1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluorophenoxymethyl)-
8
pyrrolidine-1-sulfonyl) ([18F]ICMT-11), for imaging apoptosis and/or necrosis in patients;
[18F]FDG-PET is not a marker of caspase-3/7 activation. In breast cancer, lung cancer and
lymphoma patients receiving first-line chemotherapy treatment, [18F]ICMT-11 and
cytokeratin-18 analysis (blood) were performed. [18F]ICMT-11 showed low uptake pre- and
post-chemotherapy in all tumours consistent with unremarkable changes in M30/M60
cytokeratin-18 cleavage products in the breast cohort suggesting a lack of predominantly
apoptotic cell death mechanism in responding patients. In lung cancer, multi-parametric
[18F]ICMT-11 PET/CT, diffusion weighted (DW-MRI) and dynamic contrast enhanced-MRI
(DCE-MRI) showed that PET changes were concordant with cell death in the absence of
significant perfusion changes. Thus, tumour response could occur in the absence of
predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across
entire tumour lesions. In conclusion, the optimal clinical context whereby the [18F]ICMT-11
PET endpoint critically determines the outcome of therapy remains to be established.
tool in oncology with respect to diagnosis, staging, and assessment of treatment response. We
proposed to investigate the ligand binding and retention kinetics of two novel PET/CT tracers
in human tumours that do not normally exhibit high [18F]fluorodeoxyglucose ([18F]FDG)
uptake, and a third tracer in the context of specific death mechanism. Biological validation of
the imaging endpoint included histological correlation with PET/CT data and establishment of
an optimum PET/CT methodologies for the probe for implementation into clinical practice.
The internal dosimetry and receptor-mediated tumour localisation of the ‘click’ labelled
[18F]fluoroethyl triazole octreotate analogue, [18F]FET-βAG-TOCA, in neuroendocrine
tumours (NETs) were investigated for the first time in humans. The biomarker demonstrated
favourable dosimetry, biodistribution and safety. The calculated effective dose over all subjects
(mean ± SD) was 0.029 ± 0.004 mSv/MBq. Regarding staging, [18F]FET-βAG-TOCA PET/CT
showed high tumoural uptake with high sensitivity (per lesion) compared with
[68Ga]DOTATATE PET/CT (92.8% vs 87.5%).
Tissue retention kinetics of the novel choline analogue, [18F]fluoromethyl-[1,2-2H4]-
choline ([18F]D4-FCH) were investigated in the staging of muscle invasive bladder cancer
(MIBC) and non-small cell lung cancer (NSCLC). The biomarker showed high contrast in lung
cancer but poor contrast in bladder cancer. In lung tumours, [18F]D4-FCH uptake was
quantitatively lower than [18F]FDG. Pharmacokinetic modelling revealed net tracer influx in
tumour consistent with radiotracer phosphorylation via choline kinase, however choline
kinase-alpha expression did not correlate with PET parameters.
Beyond staging, we evaluated for the first time a caspase-3/7 imaging biomarker, [18F](S)-
1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluorophenoxymethyl)-
8
pyrrolidine-1-sulfonyl) ([18F]ICMT-11), for imaging apoptosis and/or necrosis in patients;
[18F]FDG-PET is not a marker of caspase-3/7 activation. In breast cancer, lung cancer and
lymphoma patients receiving first-line chemotherapy treatment, [18F]ICMT-11 and
cytokeratin-18 analysis (blood) were performed. [18F]ICMT-11 showed low uptake pre- and
post-chemotherapy in all tumours consistent with unremarkable changes in M30/M60
cytokeratin-18 cleavage products in the breast cohort suggesting a lack of predominantly
apoptotic cell death mechanism in responding patients. In lung cancer, multi-parametric
[18F]ICMT-11 PET/CT, diffusion weighted (DW-MRI) and dynamic contrast enhanced-MRI
(DCE-MRI) showed that PET changes were concordant with cell death in the absence of
significant perfusion changes. Thus, tumour response could occur in the absence of
predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across
entire tumour lesions. In conclusion, the optimal clinical context whereby the [18F]ICMT-11
PET endpoint critically determines the outcome of therapy remains to be established.
Version
Open Access
Date Issued
2018-03
Date Awarded
2019-03
Copyright Statement
Creative Commons Attribution NonCommercial Licence
Advisor
Aboagye, Eric
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)