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

Methods: With the purpose of developing a PET imaging agent for tumors of the adrenal cortex, we developed syntheses for C-11-etomidate and its methyl analog, C-11-metomidate. (R)-[O-ethyl-1-C-11]Etomidate and (R)-[O-methyl-C-11]metomidate were prepared by reaction of the, approp riate respective C-11-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 autora diography of different tissues of the rat, pig and human. Inhibition o f tracer binding was evaluated with etomidate, ketoconazole and metyra pone, well-known inhibitors of enzymes for steroid synthesis. Tracer b inding to different human tumor samples was compared to immunohistoche mical staining with antibodies for the steroid synthesis enzymes P450 11 beta (11 beta-hydroxylase), P450 sec (cholesterol side-chain cleava ge enzyme), P450 C21 (21-hydroxylase) and P450 17 alpha (17 alpha-hydr oxylase). Three PET investigations, one with C-11-etomidate and two wi th C-11-metomidate, were performed in rhesus monkey sections, includin g the adrenals, liver and kidneys. Time-activity curves were generated from measured tracer uptake in these organs. Results: In frozen secti on autoradiography of various tissues, high binding was seen in the ad renal cortex from all species, as well as in the tumors of adrenal cor tical 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 bi nding. The adrenal binding was blocked by etomidate and ketoconazole a t low doses but not by metyrapone. The binding in the adrenal tumor sa mples correlated with immunostaining for P450 11 beta. PET studies in the monkey demonstrated high uptake in the adrenals with excellent vis ualization. The uptake increased with time without indication of washo ut. Slightly lower uptake was seen in the liver as compared to the adr enals, and in the late images, no organs other than adrenals and liver were seen. Conclusion: These investigations indicate that C-11-etomid ate and C-11-metomidate have the potential to be useful specific agent s for the visualization of the normal adrenal cortex and to provide po sitive identification of adrenal cortical tumors.