Bergström M, Bonasera T A, Lu L, Bergström E, Backlin C, Juhlin C, Långström B
Subfemtomole Biorecognition Project, Japan Sciences Technology Corporation.
J Nucl Med. 1998 Jun;39(6):982-9.
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.
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.
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.
为了开发一种用于肾上腺皮质肿瘤的正电子发射断层扫描（PET）成像剂，我们合成了11C-依托咪酯及其甲基类似物11C-甲氧基咪酯。（R）-[O-乙基-1-11C]依托咪酯和（R）-[O-甲基-11C]甲氧基咪酯是通过相应的11C标记的烷基碘与羧酸衍生物的四丁基铵盐反应制备的。通过对大鼠、猪和人类不同组织进行冷冻切片放射自显影来测试与肾上腺皮质结合的特异性。用依托咪酯、酮康唑和甲吡酮（类固醇合成酶的知名抑制剂）评估示踪剂结合的抑制情况。将示踪剂与不同人类肿瘤样本的结合情况与用类固醇合成酶P450 11β（11β-羟化酶）、P450 scc（胆固醇侧链裂解酶）、P450 C21（21-羟化酶）和P450 17α（17α-羟化酶）抗体进行的免疫组织化学染色进行比较。在恒河猴的切片（包括肾上腺、肝脏和肾脏）中进行了三项PET研究，一项使用11C-依托咪酯，两项使用11C-甲氧基咪酯。根据这些器官中测得的示踪剂摄取生成时间-活性曲线。
在各种组织的冷冻切片放射自显影中，所有物种的肾上腺皮质以及肾上腺皮质起源的肿瘤中均可见高结合。肝脏的结合水平约为肾上腺的50%，而所有其他器官的结合水平<肾上腺结合水平的10%。低剂量的依托咪酯和酮康唑可阻断肾上腺结合，但甲吡酮不能。肾上腺肿瘤样本中的结合与P450 11β的免疫染色相关。在猴子身上进行的PET研究表明，肾上腺摄取高，可视化效果极佳。摄取随时间增加，无洗脱迹象。与肾上腺相比，肝脏的摄取略低，在后期图像中，除肾上腺和肝脏外未见其他器官。
这些研究表明，11C-依托咪酯和11C-甲氧基咪酯有潜力成为用于可视化正常肾上腺皮质并对肾上腺皮质肿瘤进行阳性识别的有用特异性试剂。
