Visser T J, van Waarde A, Doze P, Elsinga P H, van der Mark T W, Kraan J, Ensing K, Vaalburg W
Positron Emission Tomography (PET) Center, Groningen University Hospital, The Netherlands.
Eur J Pharmacol. 1998 Nov 13;361(1):35-41. doi: 10.1016/s0014-2999(98)00694-3.
The agonist radioligand N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-[11C]-methoxyphenyl)-1-methylethyl]am ino]ethyl]phenyl]formamide ([11C]formoterol) was synthesised in order to test its ability to visualise pulmonary beta2-adrenoceptors in vivo, with positron emission tomography (PET). Formoterol was labelled via reaction of a dibenzyl-protected precursor with [11C]CH3I. Subsequent deprotection with Pd/C and H2 yielded [11C]formoterol in 5-15% (corrected for decay) and the specific activity ranged from 5.5-22.2 TBq mmol (150-600 Ci mmol(-1)), 60-70 min after end of bombardment. Biodistribution studies with [11C]formoterol were performed in male Wistar rats which were either untreated or predosed with (D,L)-propranolol hydrochloride (2.5 mg kg(-1), beta-adrenoceptor antagonist), erythro-DL-1-(7-methylindan-4-yloxy)-3-isopropylaminobuta n-2-ol hydrochloride (ICI 118551, 0.15 mg kg(-1), beta2-adrenoceptor antagonist), isoprenaline (15 mg kg(-1), non-subtype selective beta-adrenoceptor agonist) or (+/-)-(2-hydroxy-5-[2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl)1H-i midazol-2-yl-)phenoxy)propyl)amino)ethoxy]benzamide)monomethane sulfonate (CGP 20712A, 0.15 mg kg(-1), beta1-adrenoceptor antagonist). Lungs, heart, liver and plasma were analysed for radioactive metabolites. The kinetics of [11C]formoterol in the lungs of male Wistar rats were investigated by means of a dynamic PET study. The biodistribution studies showed significant specific binding in tissues known to contain beta2-adrenoceptors (lungs, spleen, and heart). Binding in these organs was blocked by ICI 118551 and isoprenaline, but not by CGP 20712A. [11C]Formoterol was rapidly metabolised in rats but lungs and heart did not substantially take up the labelled metabolites. The binding of [11C]formoterol in various tissues of rats is consistent with the beta2-selectivity of formoterol. Whether [11C]formoterol selectively binds to the high affinity state of beta2-adrenoceptors remains to be elucidated. [11C]Formoterol is potentially useful for studying beta2-adrenoceptors with PET and this radioligand may provide new insights in the mechanisms underlying prolonged sympathomimetic action.
合成了激动剂放射性配体N-[2-羟基-5-[1-羟基-2-[[2-(4-[¹¹C]-甲氧基苯基)-1-甲基乙基]氨基]乙基]苯基]甲酰胺([¹¹C]福莫特罗)，以便用正电子发射断层扫描(PET)在体内检测其使肺β2-肾上腺素能受体显影的能力。福莫特罗通过二苄基保护的前体与[¹¹C]CH₃I反应进行标记。随后用Pd/C和H₂脱保护，在轰击结束60 - 70分钟后得到产率为5 - 15%（校正衰变）的[¹¹C]福莫特罗，比活度范围为5.5 - 22.2 TBq/mmol(150 - 600 Ci/mmol⁻¹)。用[¹¹C]福莫特罗对雄性Wistar大鼠进行生物分布研究，这些大鼠要么未处理，要么预先给予盐酸(D,L)-普萘洛尔(2.5 mg/kg⁻¹，β-肾上腺素能受体拮抗剂)、赤藓型-DL-1-(7-甲基茚满-4-基氧基)-3-异丙氨基丁-2-醇盐酸盐(ICI 118551，0.15 mg/kg⁻¹，β2-肾上腺素能受体拮抗剂)、异丙肾上腺素(15 mg/kg⁻¹，非亚型选择性β-肾上腺素能受体激动剂)或(+/-)-(2-羟基-5-[2-((2-羟基-3-(4-((1-甲基-4-三氟甲基)1H-咪唑-2-基)苯氧基)丙基)氨基)乙氧基]苯甲酰胺)甲磺酸盐(CGP 20712A，0.15 mg/kg⁻¹，β1-肾上腺素能受体拮抗剂)。分析肺、心脏、肝脏和血浆中的放射性代谢物。通过动态PET研究考察了[¹¹C]福莫特罗在雄性Wistar大鼠肺中的动力学。生物分布研究表明，在已知含有β2-肾上腺素能受体的组织（肺、脾和心脏）中有显著的特异性结合。ICI 118551和异丙肾上腺素可阻断这些器官中的结合，但CGP 20712A不能。[¹¹C]福莫特罗在大鼠体内迅速代谢，但肺和心脏基本上不摄取标记的代谢物。[¹¹C]福莫特罗在大鼠各种组织中的结合与福莫特罗的β2选择性一致。[¹¹C]福莫特罗是否选择性结合β2-肾上腺素能受体的高亲和力状态有待阐明。[¹¹C]福莫特罗可能有助于用PET研究β2-肾上腺素能受体，这种放射性配体可能为拟交感神经作用延长的潜在机制提供新的见解。
