Quantification of [11C]Metomidate ([11C]MTO) PET
Etomidate is an imidazole-based potent inhibitor of steroid 11β-hydroxylase (mitochondrial cytochrome P450 11B1, CYP11B1) and aldosterone synthase (hydroxylase cytochrome P450, CYT11B2) , which are key enzymes in the biosynthesis of cortisol and aldosterol (Mendichovszky et al., 2016). It is used as a short-acting intravenous sedative and anaesthetic agent, because it can modulate GABAA receptors at low concentrations, and functions as an allosteric agonist at higher concentrations. Bergström et al. (1998) labelled it and its methylated version with 11C and found that the methylated version, [O-methyl-11C]metomidate, is easier to synthesize and gives better image contrast in the adrenal cortex than the labelled etomidate.
In the adrenal cortex, steroid 11β-hydroxylase is expressed in zona glomerulosa and zona fasciculata, and aldosterone synthase is expressed in zona glomerulosa.
PET imaging with [O-methyl-11C]metomidate can be used in quantification of adrenal masses and to discriminate tumors of adrenal cortical origin from non-cortical lesions (Bergström et al., 2000; Khan et al. 2003; Zettinig et al. 2004). [11C]Metomidate is useful in imaging of adrenal incidentalomas (Minn et al., 2004).
Etomidate and its close analogue (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-[18F]fluoroethylester (FETO) were shown to have potential to bind to GABAA receptors (Mitterhauser et al., 2003); same applies to [11C]MTO. GABA receptors are upregulated in hepatocellular carcinoma (HCC), but [11C]MTO did not show sufficient sensitivity for a clinical application (Roivainen et al., 2013).
Estimation of [11C]metomidate uptake
Methods for quantification of [11C]metomidate:
- Standardized uptake value (SUV) (Bergström et al., 2000; Khan et al., 2003; Zettinig et al., 2004; Hennings et al., 2006; Burton et al., 2012)
- Fractional uptake rate (FUR)
- Patlak plot (Ki) (Minn et al., 2004)
A strong relationship between SUV and Ki has been seen for all tumour types and normal adrenal glands (Minn et al., 2004).
Parent tracer is highly protein bound, while the metabolites dominate the protein free plasma; yet the plasma-to-blood ratio was about 1.2 during the 80-min study (Bergström et al., 2000). This suggests that parent tracer and its metabolites are distributed equally to the water space in the plasma and RBC.
Metomidate and etomidate are metabolized by hepatic and plasma esterases.
There are two major [11C]metomidate metabolites in plasma. The rate of their appearance varies considerably between individual patients (Minn et al., 2004). In order to calculate Patlak plot (or FUR), the plasma radioactivity concentrations must be corrected for metabolites, and unchanged fractions must be individually measured (Minn et al., 2004). Without metabolite correction, Patlak plots are not usable, and replacing plasma input with spleen as reference tissue also leads to slightly curved plots (Bergström et al., 2000).
Correction for time delay
For Patlak or FUR analysis, correction for time delay is not required.
Bergström M, Bonasera TA, Lu L, Bergström E, Backlin C, Juhlin C, Långström B. In vitro and in vivo primate evaluation of carbon-11-etomidate and carbon-11-metomidate as potential tracers for PET imaging of the adrenal cortex and its tumors. J Nucl Med. 1998; 39(6): 982-989.
Bergström M, Juhlin C, Bonasera TA, Sundin A, Rastad J, Åkerström G, Långstöm B. PET imaging of adrenal cortical tumors with the 11β-hydroxylase tracer 11C-metomidate. J Nucl Med. 2000; 41: 275-282.
Burton TJ, Mackenzie IS, Balan K, Koo B, Bird N, Soloviev DV, Azizan EA, Aigbirhio F, Gurnell M, Brown MJ. Evaluation of the sensitivity and specificity of 11C-metomidate positron emission tomography (PET)-CT for lateralizing aldosterone secretion by Conn’s adenomas. J Clin Endocrinol Metab. 2012; 97(1): 100-109.
Ettlinger DE, Wadsak W, Mien LK, Machek M, Wabnegger L, Rendl G, Karanikas G, Viernstein H, Kletter K, Dudczak R, Mitterhauser M. [18F]FETO: metabolic considerations. Eur J Nucl Med Mol Imaging. 2006; 33(8): 928-931.
Gross MD, Avram A, Fig LM, Fanti S, Al-Nahhas A, Rubello D. PET in the diagnostic evaluation of adrenal tumors. Q J Nucl Med Mol Imaging 2007; 51(3): 272-283.
Hahner S, Sundin A. Metomidate-based imaging of adrenal masses. Horm Cancer 2011; 2(6): 348-353.
Hennings J, Lindhe O, Bergström M, Långström B, Sundin A, Hellman P. [11C]Metomidate positron emission tomography of adrenocortical tumors in correlation with histopathological findings. J Clin Endocrinol Metab. 2006; 91(4): 1410-1414.
Hennings J, Hellman P, Ahlström H, Sundin A. Computed tomography, magnetic resonance imaging and 11C-metomidate positron emission tomography for evaluation of adrenal incidentalomas. Eur J Radiol. 2009; 69(2): 314-323.
Hennings J, Sundin A, Hägg A, Hellman P. 11C-metomidate positron emission tomography after dexamethasone suppression for detection of small adrenocortical adenomas in primary aldosteronism. Langenbecks Arch Surg. 2010; 395(7): 963-967.
Khan TS, Sundin A, Juhlin C, L&oring;ngström B, Bergström M, Eriksson B. 11C-metomidate PET imaging of adrenocortical cancer. Eur J Nucl Med 2003; 30: 403–410.
Kumar R, Alavi A, Fanti S. Adrenocortical positron emission tomography/PET-CT imaging. PET Clin. 2008; 2(3): 331-339.
Mendichovszky IA, Powlson AS, Manavaki R, Aigbirhio FI, Cheow H, Buscombe JR, Gurnell M, Gilbert FJ. Targeted molecular imaging in adrenal disease - an emerging role for metomidate PET-CT. Diagnostics 2016; 6(4).
Minn H, Salonen A, Friberg J, Roivainen A, Viljanen T, Långsjö J, Salmi J, Välimäki M, Någren K, Nuutila P. Imaging of adrenal incidentalomas with PET using 11C-metomidate and 18F-FDG. J Nucl Med 2004; 45:972–979.
Ouyang J, Hardy R, Brown M, Helliwell T, Gurnell M, Cuthbertson DJ. 11C-metomidate PET-CT scanning can identify aldosterone-producing adenomas after unsuccessful lateralisation with CT/MRI and adrenal venous sampling. J Hum Hypertens. 2017; 31(7): 483-484.
Powlson AS, Gurnell M, Brown MJ. Nuclear imaging in the diagnosis of primary aldosteronism. Curr Opin Endocrinol Diabetes Obes. 2015; 22(3): 150-156.
Razifar P, Hennings J, Monazzam A, Hellman P, Långström B, Sundin A. Masked volume wise principal component analysis of small adrenocortical tumours in dynamic [11C]-metomidate positron emission tomography. BMC Med Imaging 2009; 9:6.
Roivainen A, Naum A, Nuutinen H, Leino R, Nurmi H, Någren K, Parkkola R, Virtanen J, Kallajoki M, Kujari H, Ovaska J, Roberts P, Seppänen M. Characterization of hepatic tumors using [11C]metomidate through positron emission tomography: comparison with [11C]acetate. EJNMMI Res. 2013 ;3(1): 13.
Sundin A. Adrenal molecular imaging. Front Horm Res. 2016; 45: 70-79.
Zettinig G, Mitterhauser M, Wadsak W, Becherer A, Pirich C, Vierhapper H, Niederle B, Dudczak R, Kletter K. Positron emission tomography imaging of adrenal masses: 18F-fluorodeoxyglucose and the 11β-hydroxylase tracer 11C-metomidate. Eur J Nucl Med Mol Imaging 2004; 31: 1224-1230.
Created at: 2008-03-27
Updated at: 2017-10-08
Written by: Vesa Oikonen