Abstract View

Objectives:

Hypertension is the single largest risk factor contributing to the global all-cause mortality rate (1). Patients with primary aldosteronism (PA) and hypercortisolism represent the largest fraction of patients with curable secondary hypertension (2,3). In these endocrine diseases, there is an overproduction of hormones from cholesterol in one or both adrenal glands. The main pathway to identify whether the disease is unilateral or bilateral is the highly invasive procedure, adrenal vein sampling (AVS). Alternatively, positron-emission tomography (PET) offers non-invasive, functional imaging to give insight into which, or both, adrenal gland is overproducing steroids. In this study, we investigated the adrenal and liver uptake of the PET radioligand, [¹¹C]nevanimibe, which targets the steroid synthesis pathway via sterol-O-acyltransferase 1 (SOAT1) in human subjects with or without diseases of adrenal pathology.

Methods:

Following approval of the study protocol by both the UM Radioactive Drug Research Committee (RDRC) and Institutional Review Board (IRB) (HUM00265693, PI: Viglianti, approval date: 3-Apr-2025), these clinical studies commenced in 2025 and are in progress. To date, eight patients were dosed with 8-10 mCi of [¹¹C]Nevanimibe and dynamically PET imaged on a Siemens Biograph Vision 600 PET-CT from 0-15 min post-injection followed by a static PET/CT image at 30-60 min. Of the subjects, five were healthy controls (2M, 3F), one subject had congenital adrenal hyperplasia (CAH), and two patients were previously diagnosed with hypercortisolism, or Cushing’s disease (see figure) via an elevated urine free cortisol (UFC) test as well as failure to respond to adrenal suppression with dexamethasone phosphate.

Results:

In control subjects, the uptake coincides with the preclinical studies of nevanimibe in that the adrenal and liver had the highest uptake over time (4). Biliary clearance was observed with increased uptake in the gallbladder (SUV of 2.6 at 15 minutes to 24.8 at 34 min) and lack of uptake in kidneys. This is consistent with the high cLogP of the molecule at 7.1. The adrenal uptake of patients with adrenal gland disorders were compared to control subjects (see figure). In the patient with hypercortisolism, the adrenal to liver uptake ratio over time was consistently higher than the mean ratio of control subjects. Oppositely, in the subject with CAH (adrenals secrete less cortisol and aldosterone) the adrenal to liver ratio was lower than the mean of control subjects’.

Conclusions:

This work describes the first-in-human studies of the PET radioligand [¹¹C]nevanimibe. Results from this study displays consistency with results from our preclinical studies, and the expression pattern of SOAT1 (4). Initial data suggests this tracer can identify overactive adrenal glands compared to baseline uptake from control subjects. Further work is ongoing to validate the ability of the tracer to lateralize PA or Cushing’s disease and replace invasive screening with AVS.

References:

(1) Mills, K. T., et al. Nat Rev Nephrol 2020, 16 (4), 223–237.

(2) Martino M.C., et al. J Endocrinol Invest 2025, 48 (8), 1909–1918.

(3) Reincke, M., et al. The Lancet Diabetes & Endocrinology 2021, 9 (12), 876–892.

(4) Hill, J. R., et al. ACS Med. Chem. Lett. 2020, 11 (6), 1299–1304.