MU-OPIATE RECEPTORS ARE SELECTIVELY LABELED BY [H-3] CARFENTANIL IN HUMAN AND RAT-BRAIN
MU-OPIATE RECEPTORS ARE SELECTIVELY LABELED BY [H-3] CARFENTANIL IN HUMAN AND RAT-BRAIN
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DOI：
10.1016/0014-2999(89)90582-7
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发表时间：
1989-08-22
影响因子：
5
通讯作者：
STRUBLE, RG
中科院分区：
文献类型：
--
作者：
TITELER, M;LYON, RA;STRUBLE, RG
[11 C]卡芬太尼是一种有效的阿片激动剂，目前用作脑μ的特异性PET（正电子发射断层成像）扫描放射性配体。阿片受体为了详细研究卡芬太尼的受体相互作用，将[3 H]卡芬太尼用作标记大鼠和人脑组织匀浆中受体的放射性配体。发现[3 H]卡芬太尼饱和结合且具有高亲和力（KD = 0.08 ± 0.001）。0.01 nM）与由人皮质制备的膜（Bmax = 42 . ±. 3fmol/mg）和丘脑（Bmax = 84 . ±. 3fmol/mg）组织和大鼠皮质（Bmax = 82 . ±. 4fmol/mg）和间脑（Bmax = 105 . ±. 5fmol/mg）。关联（1.23 .+-. 0.19. times. 1010 Mol-1 min-1和解离速率（0.19 ± 0.15）。0.03 min-1）常数在人皮质组织中测定：来自大鼠皮质和大鼠间脑组织匀浆的研究结果产生了相似的动力学速率常数。与多种药物的竞争研究表明，[3 H]卡芬太尼主要与μ相互作用。阿片受体在四种组织中的研究;一系列非放射性阿片配体的亲和力在四种组织中基本相同（相关系数= 0.88-0.93）。纳洛酮、吗啡、DAGO（[D-Ala 2-MePhe 4-Gly-ol 5]脑啡肽）、DADL（D-Ala 2-D-Leu 5]脑啡肽）和EKC（乙基酮唑辛）以nM效力有效地显示特异性[3 H]卡芬太尼结合，而κ激动剂U-69593，σ。激动剂（+）-SKF 10047、（+）-3-PPP（（3-羟基苯基）-N-丙基哌啶）和氟哌啶醇和PCP（苯环己哌啶）是效力较低的置换剂。DAGO和吗啡相对于DADL对[3 H]卡芬太尼结合位点的更高亲和力表明δ阿片受体没有被标记。这些数据表明，[3 H]卡芬太尼是高亲和力、特异性μ C。阿片受体放射性配体，其可用于体外研究μ阿片样物质受体，并支持PET扫描数据，表明μ[11 C]卡芬太尼的阿片受体特异性。体外测定的分子动力学速率常数将有助于使用建模程序来解释PET扫描信息。
[11C]Carfentanil is a potent opioid agonist currently in use as a specific PET (position emission tomorphography) scan radioligand for brain .mu. opioid receptors. In order to investigate the receptor interactions of carfentanil in detail [3H]carfentanil was used as a radioligand for labelling receptors in rat and human brain tissue homogenates. [3H]Carfentanil was found to bind saturably and with high affinity (KD = 0.08 .+-. 0.01 nM) to membranes prepared from human cortical (Bmax = 42 .+-. 3 fmol/mg) and thalamic (Bmax = 84 .+-. 3 fmol/mg) tissues and rat cortex (Bmax = 82 .+-. 4 fmol/mg) and diencephalon (Bmax = 105 .+-. 5 fmol/mg). Association (1.23 .+-. 0.19 .times. 1010 Mol-1 min-1 and dissociation rate (0.19 .+-. 0.03 min-1) constants were determined in human cortical tissues: results from studies in rat cortical, and rat diencephalon tissue homogenates produced similar kinetic rate constants. Competitoin studies with a variety of drugs indicated that [3H]carfentanil interacts primarily with .mu. opioid receptors in the four tissues studied; the affinities of a series of non-radioactive opioid ligands were essentially identical in the four tissues (correlation coefficients = 0.88-0.93). Naloxone, morphine, DAGO ([D-Ala2-MePhe4-Gly-ol5]enkephalin), DADL (D-Ala2-D-Leu5]enkephalin) and EKC (ehtylketazocine) potently dispalced specific [3H]carfentanil binding with nM potency while the .kappa. agonist U-69593, the .sigma. agonists (+)-SKF 10047, (+)-3-PPP ((3-hydroxyphenyl)-N-propylpiperidine) and haloperidol and PCP (phencyclidine) were less potent displacing agents. The higher affinities of DAGO and morphine versus DADL for the [3H]carfentanil binding site indicates that .delta. opioid receptors are not being labelled. These data indicate that [3H]carfentanil is a high affinity, specific .mu. opioid receptor radioligand that may be of use in vitro for studying .mu. opioid receptors and supports the PET scanning data indicating the .mu. opioid receptor specificity of [11C]carfentanil. The molecular kinetic rate constants determined in vitro will be of assistance in using modelling procedures to interpret PET scanning information.