Development of a fluorine-18 radiopharmaceutical to enhance and establish adrenal imaging by positron emission tomography

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.

.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.

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.