Mitterhauser Markus, Wadsak Wolfgang, Wabnegger Leila, Sieghart Werner, Viernstein Helmut, Kletter Kurt, Dudczak Robert
Department of Nuclear Medicine, AKH Wien, University of Vienna, Vienna, Austria.
Eur J Nucl Med Mol Imaging. 2003 Oct;30(10):1398-401. doi: 10.1007/s00259-003-1252-8. Epub 2003 Jul 3.
11beta-Hydroxylase (CYP11B1, P45011beta) plays an important role in the biosynthesis of cortisol and aldosterone and has been shown to be a good target for the in vivo imaging of adrenocortical incidentalomas in nuclear medicine. [11C]Metomidate (MTO), a potent inhibitor of this enzyme, is used for positron emission tomography (PET) imaging of adrenocortical pathology. The synthesis of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-[18F]fluoroethylester (FETO), a close analogue to MTO and etomidate (ETO), has been presented recently, and the present investigation aimed to characterise the in vivo distribution of FETO. Since ETO is a well-known anaesthetic drug acting via the GABAergic system, the interaction of FETO with GABAA receptors was also evaluated. Eighteen male Sprague-Dawley rats were injected with 1.73-3.06 MBq of FETO into a tail vein after venodilatation in a 40 degrees C water bath. Rats were sacrificed by exsanguination from the abdominal aorta under deep ether anaesthesia after 10 (n=6), 30 (n=6) or 60 min (n=6); organs were removed, weighed and counted. For binding experiments, rat cerebellar membranes were incubated for 90 min at 4 degrees C in TC-50 buffer, 150 mM NaCl and 2 nM of [3H]flunitrazepam in the absence or presence of 10 microM diazepam or various concentrations of ETO, MTO and FETO. In vivo evaluation evinced very high uptake in the adrenal glands (7.52%+/-1.19% ID/g at 30 min), followed by lung (1.18%+/-0.19% ID/g, 10 min), liver (0.59%+/-0.13% ID/g, 10 min) and duodenum (0.7%+/-0.29% ID/g, 60 min). No defluorination nor fluoroethyl-ester cleavage was observed. When brain regions were compared with the thalamus (the reference region), highest relative uptake was seen in the cortex (2.34), followed by "rest brain" (2.13) and cerebellum (1.96). FETO and ETO were able to increase the binding of [3H]flunitrazepam with similar potencies and to a comparable extent. It is concluded that FETO shows characteristics suitable for the imaging of adrenocortical pathology with PET. Binding experiments on GABA receptors demonstrate a comparable effect of FETO and ETO. Hence, FETO possibly could also be used to elucidate the function, dynamics and kinetics of narcotic drugs with PET.
11β-羟化酶（CYP11B1，P45011β）在皮质醇和醛固酮的生物合成中起重要作用，并且已被证明是核医学中肾上腺皮质意外瘤体内成像的良好靶点。[11C]美托咪酯（MTO）是该酶的强效抑制剂，用于肾上腺皮质病变的正电子发射断层扫描（PET）成像。最近报道了（R）-1-（1-苯乙基）-1H-咪唑-5-羧酸2-[18F]氟乙酯（FETO）的合成，FETO是MTO和依托咪酯（ETO）的类似物，本研究旨在表征FETO的体内分布。由于ETO是一种通过GABA能系统起作用的著名麻醉药物，因此还评估了FETO与GABAA受体的相互作用。18只雄性Sprague-Dawley大鼠在40℃水浴中静脉扩张后经尾静脉注射1.73 - 3.06 MBq的FETO。在10分钟（n = 6）、30分钟（n = 6）或60分钟（n = 6）后，在深度乙醚麻醉下通过腹主动脉放血处死大鼠；取出器官，称重并计数。对于结合实验，将大鼠小脑膜在4℃下于TC-50缓冲液、150 mM氯化钠和2 nM [3H]氟硝西泮中孵育90分钟，分别在不存在或存在10μM地西泮或不同浓度的ETO、MTO和FETO的情况下进行。体内评估显示肾上腺摄取非常高（30分钟时为7.52%±1.19% ID/g），其次是肺（1.18%±0.19% ID/g，10分钟）、肝脏（0.59%±0.13% ID/g，10分钟）和十二指肠（0.7%±0.29% ID/g，60分钟）。未观察到脱氟或氟乙酯裂解。当将脑区与丘脑（参考区）进行比较时，皮质的相对摄取最高（2.34），其次是“静息脑”（2.13）和小脑（1.96）。FETO和ETO能够以相似的效力和相当的程度增加[3H]氟硝西泮的结合。结论是FETO显示出适合用PET对肾上腺皮质病变进行成像的特征。对GABA受体的结合实验表明FETO和ETO具有相当的作用。因此，FETO也可能可用于通过PET阐明麻醉药物的功能、动力学和动力学。
