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

Abstract

Methods: With the purpose of developing a PET imaging agent for tumors of the adrenal cortex, we developed syntheses for 11C-etomidate and its methyl analog, 11C-metomidate. (R)-[O-ethyl-1-11C]Etomidate and (R)-[O-methyl-11C]metomidate were prepared by reaction of the appropriate respective 11C-labeled alkyl iodide and the tetrabutylammonium salt of the carboxylic acid derivative. The specificity of binding to the adrenal cortex was tested through the use of frozen section autoradiography of different tissues of the rat, pig and human. Inhibition of tracer binding was evaluated with etomidate, ketoconazole and metyrapone, well-known inhibitors of enzymes for steroid synthesis. Tracer binding to different human tumor samples was compared to immunohistochemical staining with antibodies for the steroid synthesis enzymes P450 11beta (11beta-hydroxylase), P450 scc (cholesterol side-chain cleavage enzyme), P450 C21 (21 -hydroxylase) and P450 17alpha (17alpha-hydroxylase). Three PET investigations, one with 11C-etomidate and two with 11C-metomidate, were performed in rhesus monkey sections, including the adrenals, liver and kidneys. Time-activity curves were generated from measured tracer uptake in these organs.

Results: In frozen section autoradiography of various tissues, high binding was seen in the adrenal cortex from all species, as well as in the tumors of adrenal cortical origin. The level of liver binding was about 50% of that in the adrenals, whereas that of all other organs was <10% of the adrenal binding. The adrenal binding was blocked by etomidate and ketoconazole at low doses but not by metyrapone. The binding in the adrenal tumor samples correlated with immunostaining for P450 11beta . PET studies in the monkey demonstrated high uptake in the adrenals with excellent visualization. The uptake increased with time without indication of washout. Slightly lower uptake was seen in the liver as compared to the adrenals, and in the late images, no organs other than adrenals and liver were seen.

Conclusion: These investigations indicate that 11C-etomidate and 11C-metomidate have the potential to be useful specific agents for the visualization of the normal adrenal cortex and to provide positive identification of adrenal cortical tumors.