CETO

At least one-quarter of the UK adult population has hypertension, which is a major risk factor for heart attacks and stroke. Primary aldosteronism (PA), 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 PA in any given patient remains challenging. Existing lateralising procedures (i.e. investigations to distinguish one from two gland involvement) include computed tomography (CT) or magnetic resonance imaging (MRI). However, these often lack appropriate sensitivity and specificity, while the highly invasive adrenal vein sampling (AVS), in which small catheters are placed into each adrenal vein, is time-consuming, technically demanding, and fails in 20-50% of cases. Such diagnostic challenges have traditionally resulted in less than 300 adrenalectomies per year in the UK for PA (HES data). Therefore, there is an urgent need for an accurate and more widely available method for reliably diagnosing the cause of PA.

To address this, we have adopted a novel diagnostic approach using positron emission tomography-computed tomography (PET-CT) as an alternative to AVS. Currently, this uses metomidate labelled with carbon-11 ([₁₁C]MTO) as a radiotracer, which is taken up preferentially by the adrenal gland, and in particular by adrenal tumours causing PA. However, its utility is limited by a short tracer half-life, which means the scan can only be performed in centres with an on-site cyclotron facility (currently less than 10 NHS sites in the UK). We, therefore, wish to investigate an innovative new tracer with a longer half-life, [₁₈F]CETO, for the lateralisation of PA.

AVS is currently the gold standard for lateralisation in PA. However, it has several limitations, including technical failures and a need to discontinue confounding medications that may interfere with interpretation. These severely limit its availability and utility in routine clinical practice. Our solution to address this has been to use PET coupled with the radiopharmaceutical [11C]metomidate ([₁₁C]MTO) for molecular adrenal imaging. However, [₁₁C]MTO is limited by a short half-life (t_1/2 = 20 minutes) therefore restricting this imaging modality to facilities with an on-site cyclotron. [₁₈F]CETO has a longer half-life (t_1/2= 110 minutes). It can be distributed to centres 100-150 miles from the primary radiopharmacy site. Preclinical studies have suggested a higher adrenal selectivity with reduced uptake by adjacent organs (e.g. liver, spleen) in comparison to [₁₁C]MTO. Therefore, we anticipate [₁₈F]CETO will offer increased efficacy in PA lateralisation in addition to promoting the creation of a national network for molecular imaging in PA.

The expected dose of [₁₈F]CETO is in the range of 0.2µg to 2µg which is based on data from a validated production method as described in the investigational medicinal product (IMP) dossier. The selected dose is close to the maximum allowed, estimated from dosimetry calculations and taking into account animal in vivo studies. Based on clinical data derived from this study, we will be able to predict what dose should be sufficient to give the required signal to noise ratio, and to be used in future studies. The administration of up to 10µg of the study drug is regarded as safe due to [₁₈F]CETO being a very close analogue to the well-known registered drug Etomidate. The total radiation dose to patients participating in two [₁₈F]CETO PET-CT scans is below 10mSv which is the current standard limit for healthy controls in clinical PET research studies. There is no anticipated clinical benefit for participants in this study. This is a Proof-of-Concept study to investigate the safety and efficacy of [₁₈F]CETO.

This is a Phase 1, single-centre, open-label, micro-dosing study, conducted at Cambridge University Hospitals NHS Foundation Trust. We intend to recruit 11 participants: 5 of these subjects will be healthy controls, and 6 will be patients with PA (three with unilateral disease and three with bilateral disease as lateralised on prior AVS). Recruitment of healthy volunteers and patients will occur concurrently (i.e. it will not be necessary for all healthy volunteers to be recruited before patients will be recruited). The trial duration will be approximately 1 month.

clinicaltrials.gov

isrctn.com