First-in-human evaluation of [18F]CETO: a novel tracer for adrenocortical tumours

Abstract

Purpose: [¹¹C]Metomidate positron emission tomography (PET) is currently used for staging of adrenocortical carcinoma and for lateralization in primary aldosteronism (PA). Due to the short half-life of carbon-11 and a high non-specific liver uptake of [¹¹C]metomidate there is a need for improved adrenal imaging methods. In a previous pre-clinical study para-chloro-2-[¹⁸F]fluoroethyletomidate has been proven to be a specific adrenal tracer. The objective is to perform a first evaluation of para-chloro-2-[¹⁸F]fluoroethyletomidate positron emission computed tomography ([¹⁸F]CETO-PET/CT) in patients with adrenal tumours and healthy volunteers.

Methods: Fifteen patients underwent [¹⁸F]CETO-PET/CT. Five healthy volunteers were recruited for test-retest analysis and three out of the five underwent additional [¹⁵O]water PET/CT to measure adrenal blood flow. Arterial blood sampling and tracer metabolite analysis was performed. The kinetics of [¹⁸F]CETO were assessed and simplified quantitative methods were validated by comparison to outcome measures of tracer kinetic analysis.

Results: Uptake of [¹⁸F]CETO was low in the liver and high in adrenals. Initial metabolization was rapid, followed by a plateau. The kinetics of [¹⁸F]CETO in healthy adrenals and all adrenal pathologies, except for adrenocortical carcinoma, were best described by an irreversible single-tissue compartment model. Standardized uptake values (SUV) correlated well with the uptake rate constant K₁. Both K₁ and SUV were highly correlated to adrenal blood flow in healthy controls. Repeatability coefficients of K₁, SUV_65-70, and SUV₁₂₀ were 25, 22, and 17%.

Conclusions: High adrenal uptake combined with a low unspecific liver uptake suggests that ¹⁸F]CETO is a suitable tracer for adrenal imaging. Adrenal SUV, based on a whole-body scan at 1 h p.i., correlated well with the net uptake rate K_i.

Trial registration: ClinicalTrials.gov , NCT05361083 Retrospectively registered 29 April 2022. at, https://clinicaltrials.gov/ct2/show/NCT05361083.

Keywords: Adrenal tracer; Positron emission tomography; [18F]CETO.

Fig. 1

[¹⁸F]CETO coronal (top) and transaxial (bottom) images at 5, 15, 30 and 60 min p.i. and whole-body images at 2, 3 and 5 hours p.i.

Fig. 2

Time-activity-curves (TACs) showing the mean SUV_mean of [¹⁸F]CETO versus time post injection (x-axis). a: Normal organs/tissues b: Non-functioning adrenal adenoma, calcified), Non-functioning adrenal adenoma, Cortisol producing adenoma, aldosterone-producing adenoma/Adrenal hyperplasia, Myelolipoma, Adrenocortical carcinoma (ACC) recurrence and normal adrenal tissue. Patients with calcified non-functioning adenoma and ACC only underwent a single whole-body scan, hence no data at later time points was available

Fig. 3

ACC metastasis(arrow), patient 11. [¹⁸F]CETO PET 3 hours post injection (a) and venous phase contrast-enhanced CT performed 17 days before [¹⁸F]CETO PET (b). A high uptake of [¹⁸F]CETO is seen in the ACC metastasis (a)

Fig. 4

Right-sided Conn adenoma (arrow), patient 4. [¹⁸F]CETO PET 3 h post injection (a), arterial phase contrast-enhanced CT (b), and venous phase contrast-enhanced CT (c) where CT was performed 6 months before [¹⁸F]CETO PET

Fig. 5

Left-sided adrenal Cushing(arrow), patient 3. [¹⁸F]CETO PET 3 h post injection (a), arterial phase contrast-enhanced CT (b), and venous phase contrast-enhanced CT (c), where CT was performed 3 days after [¹⁸F]CETO PET

Fig. 6

Bilateral nonfunctional adenomas(arrows), patient 15. [¹⁸F]CETO PET 3 h post injection (a) and CT (b), where CT was performed 17 days before [¹⁸F]CETO PET

Fig. 7

a Typical blood-derived and image-derived whole-blood time-activity curves, b mean fraction of intact tracer (N = 14) and c mean plasma-whole blood ratio (N = 15). The data from a, b, and c, multiplied together, equals the input function

Fig. 8

Relationship between K₁ from the 1T1k compartment model using an IDIF (a) and an IDIF-PA (b). Black line equal to the line of identity

Fig. 9

K₁ from the 1T1k compartment model against SUV_60–70 (a) and SUV₁₂₀ (b) for adenomas (solid circles), normal adrenal tissue in patients (open circles), and healthy volunteers (blue triangles)

Fig. 10

[¹⁸F]CETO K₁-1T1k versus blood flow in the adrenal gland. Test and retest values in both adrenals are included. The solid line is a linear regression

Fig. 11

K₁-1T1k (a), SUV_60–70 (b), and SUV₁₂₀ (c) in healthy controls, normal adrenals in patients, Cushing, NFA and PA. c. controls, n. normal, p. patients The asterisk denotes significant difference (Mann-Whitney test)