Development of a fluorine-18 radiopharmaceutical to enhance and establish adrenal imaging by positron emission tomography
Lead Research Organisation:
University of Cambridge
Department Name: Wolfson Brain Imaging Centre
Abstract
Primary hyperaldosteronism (PHA) is an important, treatable form of hypertension (high blood pressure), caused by overproduction of the hormone aldosterone from the adrenal glands.
Aldosterone acts on the kidney to retain sodium ('salt'); excessive sodium retention leads to hypertension with an increased risk of stroke, heart attack and kidney failure.
PHA accounts for about 10% of patients with hypertension and 20-25% of patients whose condition is difficult to control. PHA is almost always due to a single, benign tumour (adenoma) of one adrenal gland, or diffuse 'overgrowth' of both glands (bilateral hyperplasia, BAH). Distinguishing between these is critical: surgical removal of an adenoma often cures the PHA; BAH is treated with lifelong medication.
However, at present standard investigations into the adrenal to help diagnosis, computed tomography and magnetic resonance scanning, are not sensitivity. While the other main technique adrenal vein sampling (AVS) which involves taking blood from the veins that drain both adrenal glands to measure aldosterone levels is highly invasive for patients, time-consuming, difficult to do and fails in 20-50% of cases. Therefore, there is a need for a more accurate method for diagnosing PHA, that is also less invasive.
To address this need, our solution is to use the imaging technique of positron emission tomography (PET) coupled with using a compound based on the chemical metomidate, which binds to the protein which makes aldosterone. Radioactively 'tagged' to make a radiopharmaceutical this then provide a powerful mean of imaging and assessing the adrenal gland. We have now showed this can be a powerful means to diagnosis PHA and are presently undertaking a major clinical trial to compare it with AVS.
However, at present this PET imaging technique can only be used at very few centres in the UK where the radiopharmaceutical can be prepared since it decays rapidly so must be used with 1 hr. Therefore, to enable wider access to this imaging method throughout the UK NHS our aim is to develop a new version of this radiopharmaceutical which is stable for a longer duration so can be used up to 5-6 hr after it has been manufactured. This will enable it to be prepared at one site and transported to several hospitals in a region with imaging scanners up to 100-150 mile away. Our aim in collaboration between researchers at Cambridge and Uppsala University Sweden is to develop this new radiopharmaceutical including assessing it patients with PHA.
Aldosterone acts on the kidney to retain sodium ('salt'); excessive sodium retention leads to hypertension with an increased risk of stroke, heart attack and kidney failure.
PHA accounts for about 10% of patients with hypertension and 20-25% of patients whose condition is difficult to control. PHA is almost always due to a single, benign tumour (adenoma) of one adrenal gland, or diffuse 'overgrowth' of both glands (bilateral hyperplasia, BAH). Distinguishing between these is critical: surgical removal of an adenoma often cures the PHA; BAH is treated with lifelong medication.
However, at present standard investigations into the adrenal to help diagnosis, computed tomography and magnetic resonance scanning, are not sensitivity. While the other main technique adrenal vein sampling (AVS) which involves taking blood from the veins that drain both adrenal glands to measure aldosterone levels is highly invasive for patients, time-consuming, difficult to do and fails in 20-50% of cases. Therefore, there is a need for a more accurate method for diagnosing PHA, that is also less invasive.
To address this need, our solution is to use the imaging technique of positron emission tomography (PET) coupled with using a compound based on the chemical metomidate, which binds to the protein which makes aldosterone. Radioactively 'tagged' to make a radiopharmaceutical this then provide a powerful mean of imaging and assessing the adrenal gland. We have now showed this can be a powerful means to diagnosis PHA and are presently undertaking a major clinical trial to compare it with AVS.
However, at present this PET imaging technique can only be used at very few centres in the UK where the radiopharmaceutical can be prepared since it decays rapidly so must be used with 1 hr. Therefore, to enable wider access to this imaging method throughout the UK NHS our aim is to develop a new version of this radiopharmaceutical which is stable for a longer duration so can be used up to 5-6 hr after it has been manufactured. This will enable it to be prepared at one site and transported to several hospitals in a region with imaging scanners up to 100-150 mile away. Our aim in collaboration between researchers at Cambridge and Uppsala University Sweden is to develop this new radiopharmaceutical including assessing it patients with PHA.
Technical Summary
.At least one quarter of the adult UK population has hypertension, a major risk factor for heart attacks and stroke. Primary hyperaldosteronism (PHA), a treatable form of hypertension, accounts for 5-10% of all cases, and 20-25% of those with difficult to control ('resistant') hypertension.
Determining whether one (potentially curable with surgery) or both (requiring long-term drug treatment) adrenal glands are the source of PHA in any given patient remains challenging. Existing lateralising procedures include computed tomography or magnetic resonance imaging, which often lack appropriate sensitivity, while the highly invasive adrenal vein sampling (AVS) is time-consuming, technically demanding, and fails in 20-50% of cases. Therefore, there is an urgent need for an accurate and more widely available method for reliably diagnosing the cause of PHA.
To address this need our solution is to use positron emission tomography (PET) coupled with the radiopharmaceutical [11C]metomidate for molecular adrenal imaging. We have previously shown PET can be a sensitive and specific alternative to AVS for the management of PHA. However, [11C]metomidate is labelled with the short-lived radioisotope carbon-11 (t1/2 =20 min), which limits this technique to the few PET centres in the UK with on-site radiopharmacies with cyclotrons for its manufacture.
Therefore, our objective is to overcome this barrier to wider expansion of this technique by developing a radiopharmaceutical labelled with the longer-lived radioisotope fluorine-18 (t1/2 =110 min), which can be supplied to external centres.
To achieve this, our objective is to develop [18F]CETO, a fluorine-18 analogue of metomidate, through a structured workplan with go-no go milestones, consisting of preclinical characterisation followed by PET imaging in patients.
Subsequent roll out of this radiopharmaceutical would facilitate the creation of a national NHS network for molecular imaging in PHA.
Determining whether one (potentially curable with surgery) or both (requiring long-term drug treatment) adrenal glands are the source of PHA in any given patient remains challenging. Existing lateralising procedures include computed tomography or magnetic resonance imaging, which often lack appropriate sensitivity, while the highly invasive adrenal vein sampling (AVS) is time-consuming, technically demanding, and fails in 20-50% of cases. Therefore, there is an urgent need for an accurate and more widely available method for reliably diagnosing the cause of PHA.
To address this need our solution is to use positron emission tomography (PET) coupled with the radiopharmaceutical [11C]metomidate for molecular adrenal imaging. We have previously shown PET can be a sensitive and specific alternative to AVS for the management of PHA. However, [11C]metomidate is labelled with the short-lived radioisotope carbon-11 (t1/2 =20 min), which limits this technique to the few PET centres in the UK with on-site radiopharmacies with cyclotrons for its manufacture.
Therefore, our objective is to overcome this barrier to wider expansion of this technique by developing a radiopharmaceutical labelled with the longer-lived radioisotope fluorine-18 (t1/2 =110 min), which can be supplied to external centres.
To achieve this, our objective is to develop [18F]CETO, a fluorine-18 analogue of metomidate, through a structured workplan with go-no go milestones, consisting of preclinical characterisation followed by PET imaging in patients.
Subsequent roll out of this radiopharmaceutical would facilitate the creation of a national NHS network for molecular imaging in PHA.
Planned Impact
At least one quarter of the adult UK population has hypertension, with the diseases caused by it estimated to cost the NHS over £2 billion every year (https://www.gov.uk/government/news/new-figures-show-high-blood-pressure-costs-nhs-billions-each-year). Therefore, our product has the potential to make a major impact to healthcare and NHS costs.
The successful development of our radiotracer in PHA is expected have major impact on both the individual and societal levels. These include:
1. Impact on providing a novel diagnostic tool for PHA, i.e., [18F]CETO, that generates advances in the clinic. We anticipate that the proposed strategy will ultimately lead to much enhanced screening and diagnosis of PHA with concomitant improvements in treatment regimens and overall general health.
2. Impact on the individual.
A very conservative estimate indicates the number of patients diagnosed with PHA per annum at 5,000. The benefits associated with the development of [18F]CETO are expected to have substantial impact on the management of these patients. The novel tracer will have major implications on the way PHA is diagnosed on at least a national level. Post-project roll out of this radiopharmaceutical would facilitate the creation of a national NHS network for molecular imaging in PHA, hence patients will no longer have to travel long distances to have the test performed
3. Impact on the NHS.
We are confident that successful manufacturing and suitability of [18F]CETO will have a significant impact on healthcare systems. Increased diagnosis rates for patients with unilateral PHA will allow for the successful management of the condition with improved long term intervention. We also anticipate that the overall cost of diagnosis per patients could be as much as halved following successful development of the radiotracer.
4. Impact on endocrinology research.
This project would provide a powerful imaging technique for research on the functioning of the adrenal glands, allowing for the possibility of new understanding of their disorders.
5 Commercial impact.
This study will provide essential validation for the further development and commercialisation of the novel radiotracer. The study will likely generate a valuable data package which may include protectable material but which will include ejavascript:WebForm_DoPostBackWithOptions(new WebForm_PostBackOptions("ctl00$oSaveBar$btnSave", "", true, "", "", false, true))ssential confidential information useful to a commercial partner and we thus believe that a commercial partner would choose to work with the University of Cambridge to exploit this novel diagnostic tool than work independently.
The successful development of our radiotracer in PHA is expected have major impact on both the individual and societal levels. These include:
1. Impact on providing a novel diagnostic tool for PHA, i.e., [18F]CETO, that generates advances in the clinic. We anticipate that the proposed strategy will ultimately lead to much enhanced screening and diagnosis of PHA with concomitant improvements in treatment regimens and overall general health.
2. Impact on the individual.
A very conservative estimate indicates the number of patients diagnosed with PHA per annum at 5,000. The benefits associated with the development of [18F]CETO are expected to have substantial impact on the management of these patients. The novel tracer will have major implications on the way PHA is diagnosed on at least a national level. Post-project roll out of this radiopharmaceutical would facilitate the creation of a national NHS network for molecular imaging in PHA, hence patients will no longer have to travel long distances to have the test performed
3. Impact on the NHS.
We are confident that successful manufacturing and suitability of [18F]CETO will have a significant impact on healthcare systems. Increased diagnosis rates for patients with unilateral PHA will allow for the successful management of the condition with improved long term intervention. We also anticipate that the overall cost of diagnosis per patients could be as much as halved following successful development of the radiotracer.
4. Impact on endocrinology research.
This project would provide a powerful imaging technique for research on the functioning of the adrenal glands, allowing for the possibility of new understanding of their disorders.
5 Commercial impact.
This study will provide essential validation for the further development and commercialisation of the novel radiotracer. The study will likely generate a valuable data package which may include protectable material but which will include ejavascript:WebForm_DoPostBackWithOptions(new WebForm_PostBackOptions("ctl00$oSaveBar$btnSave", "", true, "", "", false, true))ssential confidential information useful to a commercial partner and we thus believe that a commercial partner would choose to work with the University of Cambridge to exploit this novel diagnostic tool than work independently.
Organisations
- University of Cambridge (Lead Research Organisation)
- UNIVERSITY OF ABERDEEN (Collaboration)
- BARTS HEALTH NHS TRUST (Collaboration)
- GE Healthcare Limited (Collaboration)
- Central Hospital in Karlstad (Collaboration)
- St Bartholomew's Hospital (Collaboration)
- University Medical Center Gronigen (Collaboration)
Publications
García-Ortegón M
(2021)
DOCKSTRING: easy molecular docking yields better benchmarks for ligand design
García-Ortegón M
(2022)
DOCKSTRING: Easy Molecular Docking Yields Better Benchmarks for Ligand Design
in Journal of Chemical Information and Modeling
García-Ortegón M
(2022)
DOCKSTRING: Easy Molecular Docking Yields Better Benchmarks for Ligand Design.
Hird M
(2024)
Automated radiosynthesis of [18 F]CETO, a PET radiotracer for imaging adrenal glands, on Synthra RNplus.
in Journal of labelled compounds & radiopharmaceuticals
Jahan Mahabuba
(2019)
Preclinical evaluation of [
18F] CETO as a tool for the study of the adrenals
in JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS
Lubberink M.
(2021)
Radiation dosimetry of
18F-CETO, a PET tracer for adrenocortical imaging
in EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
O'Sullivan L.
(2021)
Kinetic analysis of [
18F]CETO in subjects with adrenocortical pathologies and validation of simplified quantification methods
in EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
Silins I
(2023)
First-in-human evaluation of [18F]CETO: a novel tracer for adrenocortical tumours.
in European journal of nuclear medicine and molecular imaging
Silins I
(2021)
Para-chloro-2-[18F]fluoroethyl-etomidate: A promising new PET radiotracer for adrenocortical imaging.
in International journal of medical sciences
Description | Changed our policy of handling patients with doubtful adrenal venous sampling - in whom we now perform dexametason pretreated Metomidate PET |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Current and previous PET research has changed our policy of handling patients with doubtful adrenal venous sampling - in whom we now perform dexametason pretreated Metomidate PET. Hence improvement in curing hypertension due to PHA |
Description | Co-Chair of MRC 'Black in Biomedical Research' Advisory Group |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
URL | https://www.ukri.org/who-we-are/mrc/how-we-are-governed/mrc-black-in-biomedical-research-advisory-gr... |
Description | Developing scientific career as a BME staff |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | UK PET Innovation Network |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
URL | https://www.petnetwork.org.uk/ |
Description | A prospective randomised trial comparing radio frequency ablation With laparoscopic Adrenalectomy as an alternatiVE treatment for unilateral primary aldosteronism (WAVE) |
Amount | £497,884 (GBP) |
Funding ID | CS/F/20/190025 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2021 |
End | 03/2025 |
Description | Enabling wider application of molecular imaging of pituitary adenomas through a fluorine-18 radiotracer |
Amount | £42,227 (GBP) |
Organisation | University of Cambridge |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2021 |
End | 11/2021 |
Title | Automated manufacture of the radiopharmaceutical CETO |
Description | Developed a automated manufacture method for the radiopharmaceutical CETO on GE FAsTlab module |
Type Of Material | Technology assay or reagent |
Year Produced | 2022 |
Provided To Others? | No |
Impact | an improved method for wider manufacture and dissemination of the radiopharmaceuctail |
Title | Toxicology characterisation of the compound CETO |
Description | Toxicology characterisation by micro dosing of the compound CETO to enable first in human studies |
Type Of Material | Technology assay or reagent |
Year Produced | 2018 |
Provided To Others? | No |
Impact | This will now enable this compound to be used in humans for PET research |
Description | Aberdeen NHS & University of Aberdeen nuclear medicine groups |
Organisation | University of Aberdeen |
Department | School of Medicine & Dentistry Aberdeen |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Providing information and support producing [18F]CETO at their facility |
Collaborator Contribution | Secured local funding to develop and produce [18F]CETO at their centre and are now looking to establish a national service for primary aldosteronism in Scotland. |
Impact | produce [18F]CETO at their centre and are now looking to establish a national service for primary aldosteronism in Scotland. |
Start Year | 2023 |
Description | Establishing CETO manufacture on GE FASTlab |
Organisation | GE Healthcare Limited |
Department | MDx Discovery |
Country | United Kingdom |
Sector | Private |
PI Contribution | Collaboration and expert input in developing a manufacturing method for [18F]CETU using their FASTlab radiosynthesis module |
Collaborator Contribution | Undertook the development of or [18F]CETU using their FASTlab radiosynthesis module |
Impact | Development of improved method for the radiopharmaceutical that can be widely used |
Start Year | 2021 |
Description | Groningen PET centre use of [18F]CETO |
Organisation | University Medical Center Gronigen |
Country | Netherlands |
Sector | Hospitals |
PI Contribution | Provide toxicology information to enable Groningen PET centre use the radiotracer [18F]CETO for clinical PET research |
Collaborator Contribution | obtain funding and established manufacturing of radiotracer [18F]CETO and undertaking a clinical PET project |
Impact | clinical data on [18F]CETO and publication |
Start Year | 2023 |
Description | Hosting a GE Healthcare research group |
Organisation | GE Healthcare Limited |
Department | MDx Discovery |
Country | United Kingdom |
Sector | Private |
PI Contribution | hosting in research facility |
Collaborator Contribution | financial and scientific collaboration |
Impact | N/A |
Start Year | 2021 |
Description | Supply of [18F]CETO for clinical Imaging |
Organisation | St Bartholomew's Hospital |
Department | School of Medicine and Dentistry |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | Development and manufacture of the radiopharmaceutical [18F]CETO |
Collaborator Contribution | Clinical imaging studies |
Impact | Enable for the first time the wide use of the novel radiopharmaceutical [18F]CETO for clinical diagnostic imaging |
Start Year | 2022 |
Description | Supply of [18F]CETO to Barts' hospital |
Organisation | Barts Health NHS Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | manufacture and supply of th radiotracer under GMP |
Collaborator Contribution | clinical PET studies with the radiotracer [18f]CETO |
Impact | Clinical data of [18F]CETO and research into adrenal dysfunction |
Start Year | 2023 |
Description | screening of hypertensive population to find primary aldosteronism |
Organisation | Central Hospital in Karlstad |
Country | Sweden |
Sector | Hospitals |
PI Contribution | screening of hypertensive population to find primary aldosteronism |
Collaborator Contribution | screening of hypertensive population to find primary aldosteronism |
Impact | screening of hypertensive population to find primary aldosteronism |
Start Year | 2018 |
Title | CETO Radiopharmaceutcial for imaging Adrenal Dysfunction |
Description | CETO PET radiopharmaceutcial for imaging adrenal dysfunction escepcially linked with hypertension . A successull first time in huiman study was perfomed showing the radiopharmacuticla had the good properties |
Type | Diagnostic Tool - Imaging |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2020 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Early results have been very impressive showing this new radiopharmaceutical to be superior to present method and hence is due to enter routine clinical practice this year (2021) |
Title | NHS approved [18F]CETO for clinical imaging |
Description | The radiotracer [18F]CETO has obtained temporary NHS approval to be used for clinical diagnostic studies. This represents a key milestone towards our objective of establishing [18F]CETO PET scans as an NHS technology for characterising dysfunctional adrenal glands. |
Type | Diagnostic Tool - Imaging |
Current Stage Of Development | Small-scale adoption |
Year Development Stage Completed | 2024 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | This represents a key milestone towards our objective of establishing [18F]CETO PET scans as an NHS technology for characterising dysfunctional adrenal glands. |
Description | Debate on Univeristy Racial Equalty Charter |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other audiences |
Results and Impact | Talk and debate on the aspect of the racial Equality charter and its porgression and impact within the univeristy of Cambridge |
Year(s) Of Engagement Activity | 2020 |
Description | Presentation on Total Body PET technology |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Very useful feedback on proposed reserch plan |
Year(s) Of Engagement Activity | 2022 |
Description | Presentation to Schmidt Felowship |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | talk and dicussion with Schmidt Science Fellows . The aim to create a new generation of scientific leaders with vision is to give the world's best aspiring scientific minds a broader perspective, the ability to engage in an interdisciplinary way, and the opportunity to make a lasting impact on society |
Year(s) Of Engagement Activity | 2020 |
Description | Presentation to The Royal Society of Medicine |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation in the development and application of [18F]CETO for clinical diagnosis of primary aldosteronism |
Year(s) Of Engagement Activity | 2023 |
Description | Progress in Primary Aldosteronism |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | An invited talk to dicuss the applcation of molecular imaging to clincal care of aldosterism |
Year(s) Of Engagement Activity | 2019 |
Description | Webinar to Society of Neuroscientists of Africa |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Talk and dicussion on aspect of being a BAME scientist to the Society of Neuroscientists of Africa (SONA) is the umbrella organisation for the regional and national neuroscience societies and groups in Africa, |
Year(s) Of Engagement Activity | 2020 |
URL | http://www.youtube.com/channel/UCvSiEt9aShrhpC6u86yBsgw |