Development of new carbon-11 labelled radiotracers for imaging GABAA- and GABAB-benzodiazepine receptors
Development of new carbon-11 labelled radiotracers for imaging GABAA- and GABAB-benzodiazepine receptors
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DOI：
10.1016/j.bmc.2012.05.046
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发表时间：
2012-07-15
影响因子：
3.5
通讯作者：
Vasdev, Neil
中科院分区：
文献类型：
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作者：
Moran, Matthew D.;Wilson, Alan A.;Vasdev, Neil
两种喹啉类被鉴定为γ-氨基丁酸（GABA）（A）受体的正向别构调节剂，含有α（2）亚基，9-氨基-2-环丁基-5-甲基-N-氨基丁酸（GABA）（A）受体。（6-甲氧基-2-甲基吡啶-3-基）-2，3-二氢-1H-吡咯并[3，4-B]喹啉-1-酮（4）和9-氨基-2-环丁基-5-（三氟甲基）吡啶-3-基）-2，3-二氢-1H-吡咯并[3，4-b]喹啉-1-酮（4）。（2-甲氧基吡啶-3-基）-2，3-二氢-1H-吡咯并[3，4-B]喹啉-1-酮（5）在甲氧基位置用碳-11进行放射性标记（半衰期= 20.4 min）。这些喹啉类化合物代表了一类新的潜在放射性示踪剂，可用于正电子发射断层扫描（PET）对GABA（A）受体的苯二氮卓类位点进行成像。两种放射性示踪剂在其各自的吡啶酮/吡啶醇互变异构体前体与临床上有用的配制量的[C-11] CH 3 I反应后可靠地分离（相对于[C-11]CO2，未校正放射化学产率分别为2.9%和2.7%），具有高比活度（>70 GBq μ mol（1）; >2 Ci μ mol（-1））和高放射化学纯度（>95%）。本文报道的放射合成代表了选择性分离带有[C-11]2-甲氧基吡啶部分的放射性标记化合物的罕见实例。尽管基于在清醒啮齿动物中的初步离体生物分布研究，两种放射性示踪剂均表现出有希望的成像特性，但观察到[C-11]5的脑摄取较高，因此进一步评价了该放射性示踪剂。碳-11标记的5容易穿透大脑（在注射放射性示踪剂后15分钟，在皮质区域中>1个标准摄取值），具有似乎可逆的GABA（A）受体的适当脑区域分布，并且在注射后15分钟内，在大鼠脑匀浆中未显示任何明显的放射性代谢。预先给药氟马西尼（1，10 mg kg（1））或5（5 mg kg（1））可有效阻断>50%的[C-11]5与GABA（A）受体富集区的结合，从而表明这种放射性示踪剂值得进一步评价用于GABA（A）受体显像。此外，使用[C-11]甲基碘一步有效标记GABA（B）受体的变构调节剂（R，S）-N-（1-（3-氯-4-甲氧基苯基）乙基）-3，3-二苯基丙-1-胺6。在清醒大鼠中的离体生物分布研究显示脑摄取较低，因此，正在努力发现替代放射性示踪剂以成像GABA（B）。总之，[C-11]5值得在高等动物中进一步评价，用于中枢神经系统中GABA（A）受体的成像。由爱思唯尔有限公司发布
Two quinolines identified as positive allosteric modulators of gamma-aminobutyric acid (GABA)(A) receptors containing the alpha(2) subunit, 9-amino-2-cyclobutyl-5-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (4) and 9-amino-2-cyclobutyl-5-(2-methoxypyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (5), were radiolabelled at the methoxy position with carbon-11 (half-life = 20.4 min). These quinolines represent a new class of potential radiotracers for imaging the benzodiazepine site of GABA(A) receptors with positron emission tomography (PET). Both radiotracers were reliably isolated following reaction of their respective pyridinone/pyridinol tautomeric precursors with [C-11]CH3I in clinically useful, formulated quantities (2.9% and 2.7% uncorrected radiochemical yield, respectively, relative to [C-11]CO2) with high specific activities (>70 GBq mu mol (1); >2 Ci mu mol(-1)) and high radiochemical purities (>95%). The radiosyntheses reported herein represent rare examples of selectively isolating radiolabelled compounds bearing [C-11]2-methoxypyridine moieties. Although both radiotracers demonstrated promising imaging characteristics based on preliminary ex vivo biodistribution studies in conscious rodents, higher brain uptake was observed with [C-11]5 and therefore this radiotracer was further evaluated. Carbon-11 labelled 5 readily penetrated the brain (>1 standard uptake value in cortical regions at 15 min post-injection of the radiotracer), had an appropriate regional brain distribution for GABA(A) receptors that appeared to be reversible, and did not show any appreciable radiometabolites in rat brain homogenates up to 15 min post-injection. Preadministration of flumazenil (1, 10mg kg (1)) or 5 (5 mg kg (1)) effectively blocked >50% of [C-11]5 binding to the GABA(A) receptor-rich regions, thereby suggesting that this radiotracer is worthy of further evaluation for imaging GABA(A) receptors. Additionally (R,S)-N-(1-(3-chloro-4-methoxyphenyl)ethyl)-3,3-diphenylpropan-1-amine, 6, an allosteric modulator of GABA(B) receptors, was efficiently labelled in one step using [C-11]methyl iodide. Ex vivo biodistribution studies in conscious rats showed low brain uptake, therefore, efforts are underway to discover alternative radiotracers to image GABA(B). In conclusion, [C-11]5 is worthy of further evaluation in higher species for imaging GABA(A) receptors in the central nervous system. Published by Elsevier Ltd.