Periodic Reporting for period 1 - DDG-MRI (DDG-MRI for cancer detection - A novel medical imaging approach that correlates to FDG-PET without ionising radiation)
Période du rapport: 2024-12-01 au 2025-11-30
Positron emission tomography (PET) measurements of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake have been widely used clinically for tumor /staging, prognosis, and treatment monitoring, where it can be more sensitive at detecting treatment response than magnetic resonance imaging (MRI) and computerized tomography (CT) -based evaluations of tumor size. 2-deoxy-D-glucose (DG) and FDG are non-metabolizable derivatives of D-glucose that get trapped in the cells of active or malignant tissues. Although highly sensitive, ionizing radiation associated with FDG-PET limits its frequent use (typically no more than 2-3 examinations per year) and its application in populations such as children and pregnant women, who may otherwise benefit from this valuable and unique diagnostic imaging examination. As such, alternative techniques are in high demand.
The DDG-MRI project aims to provide the benefits of FDG-PET without ionizing radiation. We propose an MRI-based imaging agent and technique that will give PET-like images without ionizing radiation. To this end, we will make use of 1) a novel DG analogue that is labelled with deuterons (deuterated-2-deoxy-D-glucose, or DDG), and 2) rapid and sensitive deuterium MRI schemes targeted at demonstrating the uptake of this agent in malignant tissues, following intravenous administration. The DDG-MRI technology is likely to be quickly adopted by medical centers as it does not require significant hardware changes, does not change the MRI suite workflow, and is expected to cost the same as a PET scan. This consortium comprises six partners, two of whom are industrial partners, from five countries, who are enthusiastic about making DDG-MRI a medical reality for cancer detection and treatment monitoring.
For more information, please go to www.ddg-mri.org
The DDG-MRI project aims to provide the benefits of FDG-PET without ionizing radiation. We propose an MRI-based imaging agent and technique that will give PET-like images without ionizing radiation. To this end, we will make use of 1) a novel DG analogue that is labelled with deuterons (deuterated-2-deoxy-D-glucose, or DDG), and 2) rapid and sensitive deuterium MRI schemes targeted at demonstrating the uptake of this agent in malignant tissues, following intravenous administration. The DDG-MRI technology is likely to be quickly adopted by medical centers as it does not require significant hardware changes, does not change the MRI suite workflow, and is expected to cost the same as a PET scan. This consortium comprises six partners, two of whom are industrial partners, from five countries, who are enthusiastic about making DDG-MRI a medical reality for cancer detection and treatment monitoring.
For more information, please go to www.ddg-mri.org
The objectives of the project are:
To optimize the synthesis of DDG and study the human regulatory aspects of DDG.
To develop and optimize the hardware and software required for deuterium MRI acquisition of DDG on clinical MRI 3T scanners.
To investigate the accumulation of DDG in pre-clinical models and determine the effective dose for this agent and its utility.
To disseminate the results of the project to stakeholders and to develop a strategy for the commercialization of the DDG contrast agent and the DDG-MRI technology as a tool for cancer detection and treatment monitoring.
To ensure the legal, financial, and day-to-day activities necessary for the project.
The progress made towards these goals by the DDG-MRI partners in the first year is summarized below:
HMO
HMO has been coordinating all project activities, including meetings, contracts, grant applications, deliverable submissions, and milestone achievements.
Experimentally, HMO has completed a study of perfused rat brain slices incubated with deuterated glucose. This work was published in NMR in Biomedicine. Continuation of the work with DDG is performed with the DDG compounds provided by CortecNet. This work aims to give biodistribution and preliminary safety data. The initial results are:
1. In rats, intravenously injected with a dose of 37 to 55 mg/kg [D4]DDG, the concentration of the accumulated [D4]DDG in the brain was 0.51 ± 0.14 mM (n=3, assumed to be [D4]DDG-6-phosphate).
2. Mice and rats (n=36) showed no adverse effects to bolus intravenous injections of [D2], [D4], and [D8]DDG at doses ranging from 37 mg/kg to 248 mg/kg (dose equivalent to 2DG mg/kg). The animals were observed awake for up to 78 min after the injection.
CortecNet
CortecNet has developed synthesis routes to produce a series of deuterated 2-deoxyglucose (DDG) analogs: [D2]DDG, [D4]DDG, [D5]DDG, [D7]DDG, and [D8]DDG. All compounds were produced at a gram scale with an average deuterium enrichment above 94% and chemical purity > 99%, with ethanol as the observed impurity. All products were shipped to partners for evaluation. The compound [3,4,6,6-D4]DDG was selected for further development.
UULM
A small animal holder (Fig. 1. a) was integrated in clinical MRI systems. The physiological monitoring interface to the clinical scanners (Fig. 1. b) was tested and validated on a 3T Philips (Fig. 1. c, top) and 3T Siemens (Fig. 1. c, bottom) clinical scanners. Two dedicated radiofrequency 2H coil designs were developed and evaluated for a 3T Philips clinical system: (Fig. 2. a) a whole-body solenoid coil, and (Fig. 2. b) a double-turn loop coil. Using this optimized setup, we demonstrated the first 2H in-vivo CSI imaging experiments in mice in a 3T clinical scanner at natural abundance (Fig. 2. c). The first in-vivo measurements employing a single-loop local T/R coil centered at the head of the animal are shown in Fig. 3. Initial phantom experiments conducted to distinguish HDO from [D4]DDG based on their different T1 relaxation times are shown in Fig. 4.
The first in vivo experiments in mice were performed using [D4]DDG in a 3T clinical scanner. Following injection, an apparent increase in signal was observed, reaching a stable plateau approximately 30 minutes post-injection. This elevated signal remained stable for at least 60 minutes (Fig. 5).
DTU
The 2H coils are based on a solenoid design perpendicular to the MR scanner magnet's axis. The solenoid has high sensitivity compared to other designs, despite being linearly polarized. The solenoid is used as a transmit and receive coil. The solenoid is single-tuned and decoupled from the 1H field of the body coil or another volume coil in which the sample can be placed. This allows for 1H anatomical imaging while optimizing the 2H sensitivity.
The mouse coil has an inner diameter of 40 mm, and the rat coil has an inner diameter of 72 mm. A standard design for the transmit and receive switch (TR switch) has been developed. The two coils perform as expected and can be used for animal studies at HMO. A specialty phantom was prepared for benchmarking, cross-site comparison, and quality assurance. The coil has been tested at DTU (DK), GE (DE), and has been delivered to HMO (IL) for further work.
UNITO
All DDG compounds were characterised by high-resolution NMR spectroscopy at 9.4 T and showed the expected resonances corresponding to the different degrees of deuteration. The T₁s of the various DDG molecules were determined at 37 °C. Initial DDG-MRI experiments were performed on a phantom containing four vials of water, [D2]DDG, [D4]DDG, and [D7]DDG, each at 300 mM. The DDG signal collapses into a single resonance, which is quantitative with respect to both the number of deuterons per molecule and the DDG concentration. The naturally abundant deuterium signal from water did not interfere with the detection or quantification of the DDG signal.
DDG was administered intravenously to healthy mice. The DDG signal in the brain reached a maximum 15 minutes after administration, while the stable post-washout concentration was approximately 2.7±0.2 mM. No significant differences in brain uptake or kinetic behaviour were observed when comparing DDG compounds with different degrees of deuteration ([D2]DDG versus [D7]DDG). As expected, no HDO production was detected following DDG injection, whereas glucose administration increased the HDO signal. DDG exhibited stable accumulation in brain tissue over time, consistent with its non-metabolizable nature.
To optimize the synthesis of DDG and study the human regulatory aspects of DDG.
To develop and optimize the hardware and software required for deuterium MRI acquisition of DDG on clinical MRI 3T scanners.
To investigate the accumulation of DDG in pre-clinical models and determine the effective dose for this agent and its utility.
To disseminate the results of the project to stakeholders and to develop a strategy for the commercialization of the DDG contrast agent and the DDG-MRI technology as a tool for cancer detection and treatment monitoring.
To ensure the legal, financial, and day-to-day activities necessary for the project.
The progress made towards these goals by the DDG-MRI partners in the first year is summarized below:
HMO
HMO has been coordinating all project activities, including meetings, contracts, grant applications, deliverable submissions, and milestone achievements.
Experimentally, HMO has completed a study of perfused rat brain slices incubated with deuterated glucose. This work was published in NMR in Biomedicine. Continuation of the work with DDG is performed with the DDG compounds provided by CortecNet. This work aims to give biodistribution and preliminary safety data. The initial results are:
1. In rats, intravenously injected with a dose of 37 to 55 mg/kg [D4]DDG, the concentration of the accumulated [D4]DDG in the brain was 0.51 ± 0.14 mM (n=3, assumed to be [D4]DDG-6-phosphate).
2. Mice and rats (n=36) showed no adverse effects to bolus intravenous injections of [D2], [D4], and [D8]DDG at doses ranging from 37 mg/kg to 248 mg/kg (dose equivalent to 2DG mg/kg). The animals were observed awake for up to 78 min after the injection.
CortecNet
CortecNet has developed synthesis routes to produce a series of deuterated 2-deoxyglucose (DDG) analogs: [D2]DDG, [D4]DDG, [D5]DDG, [D7]DDG, and [D8]DDG. All compounds were produced at a gram scale with an average deuterium enrichment above 94% and chemical purity > 99%, with ethanol as the observed impurity. All products were shipped to partners for evaluation. The compound [3,4,6,6-D4]DDG was selected for further development.
UULM
A small animal holder (Fig. 1. a) was integrated in clinical MRI systems. The physiological monitoring interface to the clinical scanners (Fig. 1. b) was tested and validated on a 3T Philips (Fig. 1. c, top) and 3T Siemens (Fig. 1. c, bottom) clinical scanners. Two dedicated radiofrequency 2H coil designs were developed and evaluated for a 3T Philips clinical system: (Fig. 2. a) a whole-body solenoid coil, and (Fig. 2. b) a double-turn loop coil. Using this optimized setup, we demonstrated the first 2H in-vivo CSI imaging experiments in mice in a 3T clinical scanner at natural abundance (Fig. 2. c). The first in-vivo measurements employing a single-loop local T/R coil centered at the head of the animal are shown in Fig. 3. Initial phantom experiments conducted to distinguish HDO from [D4]DDG based on their different T1 relaxation times are shown in Fig. 4.
The first in vivo experiments in mice were performed using [D4]DDG in a 3T clinical scanner. Following injection, an apparent increase in signal was observed, reaching a stable plateau approximately 30 minutes post-injection. This elevated signal remained stable for at least 60 minutes (Fig. 5).
DTU
The 2H coils are based on a solenoid design perpendicular to the MR scanner magnet's axis. The solenoid has high sensitivity compared to other designs, despite being linearly polarized. The solenoid is used as a transmit and receive coil. The solenoid is single-tuned and decoupled from the 1H field of the body coil or another volume coil in which the sample can be placed. This allows for 1H anatomical imaging while optimizing the 2H sensitivity.
The mouse coil has an inner diameter of 40 mm, and the rat coil has an inner diameter of 72 mm. A standard design for the transmit and receive switch (TR switch) has been developed. The two coils perform as expected and can be used for animal studies at HMO. A specialty phantom was prepared for benchmarking, cross-site comparison, and quality assurance. The coil has been tested at DTU (DK), GE (DE), and has been delivered to HMO (IL) for further work.
UNITO
All DDG compounds were characterised by high-resolution NMR spectroscopy at 9.4 T and showed the expected resonances corresponding to the different degrees of deuteration. The T₁s of the various DDG molecules were determined at 37 °C. Initial DDG-MRI experiments were performed on a phantom containing four vials of water, [D2]DDG, [D4]DDG, and [D7]DDG, each at 300 mM. The DDG signal collapses into a single resonance, which is quantitative with respect to both the number of deuterons per molecule and the DDG concentration. The naturally abundant deuterium signal from water did not interfere with the detection or quantification of the DDG signal.
DDG was administered intravenously to healthy mice. The DDG signal in the brain reached a maximum 15 minutes after administration, while the stable post-washout concentration was approximately 2.7±0.2 mM. No significant differences in brain uptake or kinetic behaviour were observed when comparing DDG compounds with different degrees of deuteration ([D2]DDG versus [D7]DDG). As expected, no HDO production was detected following DDG injection, whereas glucose administration increased the HDO signal. DDG exhibited stable accumulation in brain tissue over time, consistent with its non-metabolizable nature.