With the advent and evolution of modern imaging techniques, there has been an increase in the detection of adrenal lesions, most often incidentally (4–7% of all abdominal CT scans in patients >40 y). Computed tomography (CT) is generally preferred for the evaluation of adrenal masses, and often informs treatment decisions (e.g., surgical resection) by establishing lesion size, density and homogeneity. However, anatomical imaging provides limited or no information regarding the functional status of an adrenal mass, which is a key element in the decision-making process, particularly with respect to recommending surgery, and in guiding pre-, peri- and postoperative endocrine management. These challenges are exemplified by primary aldosteronism (PA), a condition caused by autonomous aldosterone secretion from one or both adrenal glands, and which accounts for between 5–14% of all hypertension. Distinguishing between unilateral and bilateral disease is a key step in the management pathway as it identifies those patients who might benefit from unilateral adrenalectomy to effect cure of biochemical hyperaldosteronism with reversal or amelioration of hypertension (± hypokalaemia). Adrenal vein sampling (AVS) remains the current gold standard for lateralisation (i.e. determining whether one or both adrenal glands are implicated). However, it is limited by its invasive nature and the requirement for an experienced interventional radiologist, given the challenges associated with successfully cannulating the right adrenal vein. Accordingly, alternative techniques for distinguishing unilateral and bilateral causes of PA have been proposed, including adrenal molecular imaging with the positron emission tomography radiotracer [¹¹C]Metomidate (MTO PET). MTO has previously been shown to have high affinity for adrenocortical tissue (targeting the key enzymes CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase).

This thesis examines the potential roles for molecular adrenal imaging with MTO PET in the management of (i) adrenal incidentalomas which are deemed indeterminate on conventional anatomical imaging, and (ii) in patients with PA. However, an important limitation of MTO is the requirement for an on-site cyclotron due to the short half-life (t½=20mins) of Carbon-11, which potentially limits the application of this imaging modality to a relatively small number of NHS sites across the UK. Therefore, this thesis also describes first-in-human studies with a related novel radiotracer [¹⁸F]CETO, which has a longer half-life (t½=110mins), to determine whether it has the potential to facilitate more widespread access to molecular adrenocortical imaging.

The first chapter summarises the current knowledge base, including providing an overview of the current literature pertaining to adrenal adenomas and available imaging modalities, with a particular focus on molecular imaging modalities. Chapter two describes the methods that are common among the research studies presented in the subsequent chapters. Chapter three highlights the role of MTO PET in enhancing decision-making and improving outcomes for a proportion of cases where conventional imaging may fail to accurately characterise adrenal incidentalomas (AIs). This chapter highlights how MTO can be used to distinguish the origin of the indeterminate AI, and how a combination of imaging modalities [e.g., FDG PET, ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG)] can be used to characterise (a) the origin of the lesion i.e., adrenocortical or non-adrenocortical, and (b) determine the malignant potential of the lesion. This will increase the accuracy in detection of the underlying adrenal pathology associated with the AI, and in turn better guide the diagnostic pathway and proposed management of AIs, along with determining the prospective scanning frequency. In certain instances, I demonstrate how a combination of two imaging modalities may avert the need for unnecessary adrenal biopsy, which is commonly associated with low yield and often non-diagnostic, and unnecessary surgical resection. I then focus specifically on PA, with chapter four outlining the ability of MTO PET/CT to accurately distinguish between unilateral and bilateral disease, using either MTO alone, or in combination with AVS findings, to guide surgical management in PA patients through a retrospective series. The findings of the study permitted the creation of a decision matrix, so that clinicians can adopt a more systematic approach in using MTO PET/CT to guiding the decision to proceed to surgery. The positive findings from the retrospective study described in chapter four required validation in a prospective study design, which is addressed in the subsequent chapter. Chapter five describes a prospective multicentre study, MATCH, which evaluates the role of MTO PET/CT for lateralisation in PA by comparing findings with the current gold standard, AVS. Following on from both retrospective and prospective studies, a limitation that has been identified with reference to MTO is the short half-life, restricting synthesis to clinical sites with an on-site cyclotron which amounts to <10 NHS clinical sites. To overcome this limitation, a fluorinated radiotracer will possess a significant advantage, permitting distribution of the tracer to neighbouring clinical sites as far as 100-150miles away, and increasing accessibility to molecular imaging in a wider geographical area. Chapter six focuses on a first-in-human phase I clinical trial evaluating the efficacy and safety of a novel molecular tracer, [¹⁸F]CETO, comprising of five healthy volunteers and six PA patients (three unilateral and three bilateral disease). We assess the safety, tolerability, and efficacy of the tracer, and adopt dexamethasone administration in the protocol to determine how this impacts on the signal-to-noise ratio. Additionally, dosimetry calculations were undertaken to determine how tracer uptake compares in different organs. Throughout the studies described, adrenal specimens were taken and analysed to confirm aldosterone-producing adenoma(s), and whether the type of lesion correlates with the pattern of tracer uptake of the radiotracer. However, only a small number of studies in the current literature have outlined how certain histopathological characteristics may also correlate with other factors in PA, including pre- and postoperative outcomes. I conclude with chapter 7, which describes how specific histopathological findings in PA may correlate with pre- and postoperative outcomes. I take advantage of our retrospective patient cohort, of which a significant proportion would have proceeded to MTO to determine the appropriateness of surgical intervention. Therefore, I was able to assess the relationship between histopathological features on resected adrenal specimens, and the pattern of MTO tracer uptake on PET imaging.