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. 2021 Mar 21;18(10):2187-2196.
doi: 10.7150/ijms.51206. eCollection 2021.

Para-chloro-2-[18F]fluoroethyl-etomidate: A promising new PET radiotracer for adrenocortical imaging

Isabella Silins  1 , Anders Sundin  1 , Patrik Nordeman  2 , Mahabuba Jahan  2 , Sergio Estrada  2 , Azita Monazzam  3 , Mark Lubberink  1 , Franklin Aigbirhio  4 , Per Hellman  1 , Gunnar Antoni  2
Affiliations

Para-chloro-2-[18F]fluoroethyl-etomidate: A promising new PET radiotracer for adrenocortical imaging

Isabella Silins et al. Int J Med Sci. .

Abstract

Introduction: [11C]Metomidate ([11C]MTO), the methyl ester analogue of etomidate, was developed as a positron emission tomography (PET) radiotracer for adrenocortical tumours and has also been suggested for imaging in primary aldosteronism (PA). A disadvantage of [11C]MTO is the rather high non-specific binding in the liver, which impacts both visualization and quantification of the uptake in the right adrenal gland. Furthermore, the short 20-minute half-life of carbon-11 is a logistic challenge in the clinical setting. Objectives: The aim of this study was to further evaluate the previously published fluorine-18 (T1/2=109.5 min) etomidate analogue, para-chloro-2-[18F]fluoroethyl etomidate; [18F]CETO, as an adrenal PET tracer. Methods: In vitro experiments included autoradiography on human and cynomolgus monkey (non-human primate, NHP) tissues and binding studies on adrenal tissue from NHPs. In vivo studies with [18F]CETO in mice, rats and NHP, using PET and CT/MRI, assessed biodistribution and binding specificity in comparison to [11C]MTO. Results: The binding of [18F]CETO in the normal adrenal cortex, as well as in human adrenocortical adenomas and adrenocortical carcinomas, was shown to be specific, both in vitro (in humans) and in vivo (in rats and NHP) with an in vitro Kd of 0.66 nM. Non-specific uptake of [18F]CETO in NHP liver was found to be low compared to that of [11C]MTO. Conclusions: High specificity of [18F]CETO to the adrenal cortex was demonstrated, with in vivo binding properties qualitatively surpassing those of [11C]MTO. Non-specific binding to the liver was significantly lower than that of [11C]MTO. [18F]CETO is a promising new PET tracer for imaging of adrenocortical disease and should be evaluated further in humans.

Keywords: 18F-CETO; Adrenal masses; Adrenal tracer; Positron emission tomography; Primary aldosteronism.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Displays the molecular structure of A: [11C]MTO & [18F]FETO, B: [18F]CDP2230 and C: [18F]FAMTO.
Figure 2
Figure 2
Radiosynthesis of [18F]CETO.
Figure 3
Figure 3
Tissue uptake of [18F]CETO (nmol/mm2) from the results of three separate autoradiography experiments A-C. The immunohistochemical expression of CYP11B1/-B2 is noted as B1/B2 positive (+) or negative (-). Abbrevations used in figure: ACC: adrenocortical carcinoma (A, C), APA: adrenocortical adenoma (B, C), CPA: cortisol-producing adenoma (A, C), NHP: non-human primate (A, B), PCC: pheochromocytoma (A, C). Note that the presented values can only be compared within each separate heat map: A, B or C.
Figure 4
Figure 4
A & B: Saturation curves, from two separate experiments, generated Bmax and Kd values for [18F]CETO. The graphs show the binding of [18F]CETO to CYP11B1 and CYP11B2 in NHP adrenal gland homogenate. Total binding (black line), non-specific binding (dark grey interrupted line) and specific binding (light grey), were obtained by non-linear regression analysis of the data in GraphPad Prism 8.2. Specific binding values were obtained by subtracting the non-specific binding from the total binding. The values represent the mean ± standard error of the experiment, which was performed using triplicates.
Figure 5
Figure 5
[18F]CETO in vivo biodistribution in female mice (N=4 per group), without (black bar) or with (grey bar) metomidate blocking, here expressed as tissueSUV/adrenalSUV ratios, with individual ratios to be compared with 1 (adrenalSUV/ adrenalSUV).
Figure 6
Figure 6
Ex-vivo biodistribution of [18F]CETO in rats. A: male rats, B: female rats; n= 3 per timepoint, with the exception of B at 30 min where n= 1.Data are expressed as tissueSUV/adrenalSUV ratios, with individual ratios to be compared with 1 (adrenalSUV/ adrenalSUV).
Figure 7
Figure 7
Representative sagittal PET-MR images of mice injected with [18F]CETO, SUV 30 min post injection. A: At baseline. B: After blockage with metomidate, 1μmol/kg.
Figure 8
Figure 8
Representative coronal PET (A) and PET/MRI fusion (B, C, D) SUV images in rat 30 min post injection of [18F]CETO (A, B) and [18F]FETO (C, D), without (A, C) and with (B, D) blockage with 1μmol/kg metomidate.
Figure 9
Figure 9
Representative sagittal (upper panel) and transverse (lower panel) PET images in NPH. A-C: SUV images 60-85 min post tracer injection. D-E: Net uptake rate (Patlak). A: [11C]MTO, B: [18F]CETO, C: [18F]CETO after blockage with etomidate 0.5 mg/kg, D: [18F]CETO, E: [18F]CETO after blockage with etomidate 0.5 mg/kg.
Figure 10
Figure 10
Fraction of intact [18F]CETO in venous plasma from NHP, at baseline (black line) and after etomidate blocking (pink line).
Figure 11
Figure 11
TACs showing the SUVmean over time in various NHP organs. A: the peak uptake of [11C]MTO in the adrenal glands was seen at approximately 40 min p.i. B: the peak uptake of [18F]CETO in the adrenal glands was still not reached at the end of scanning 85 min p.i. C: [18F]CETO after blocking with etomidate.
Figure 12
Figure 12
TACs (dots) and irreversible two-tissue compartment model fits for [18F]CETO in the adrenal glands at baseline (teal line) and after blocking with etomidate (black line).
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