NONINVASIVE QUANTIFICATION OF MUSCARINIC RECEPTORS INVIVO WITH POSITRON EMISSION TOMOGRAPHY IN THE DOG HEART
NONINVASIVE QUANTIFICATION OF MUSCARINIC RECEPTORS INVIVO WITH POSITRON EMISSION TOMOGRAPHY IN THE DOG HEART
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DOI：
10.1161/01.cir.82.4.1494
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发表时间：
1990-10-01
期刊：
影响因子：
37.8
通讯作者：
MAZOYER, BM
中科院分区：
文献类型：
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作者：
DELFORGE, J;JANIER, M;MAZOYER, BM
在体内定量心肌毒蕈碱受体已获得在六个闭胸狗通过使用正电子发射断层扫描。给狗注射痕量的11 C标记的二苯羟乙酸甲基奎宁环酯（MQNB），一种非代谢的毒蕈碱受体拮抗剂。30分钟后，注射过量的未标记的MQNB（置换实验）。在70和120分钟后分别注射两次未标记的MQNB与[11 C]MQNB（共注射实验）和无[11 C]MQNB（第二次置换实验）。该方案允许单独评价每只狗中可用受体的量（B“max）以及结合和解离速率常数（k+1和k-1）。通过使用非线性数学模型在左心室和室间隔上的感兴趣区域中计算参数。B_（max）平均值为42. ±. 11 pmol/ml组织时，速率常数k+1、k-1和Kd为0.6 ± 0.5。0.1 ml. cntdot. pmol-1.cntdot. min ~（-1），0.27 ±。0.03 ml. cntdot. pmol-1.cntdot. min-1，0.49 ±-. 0.14 pmol. cntdot. ml-1，考虑到MQNB反应体积估计为0.15 ml/ml组织。虽然[11 C]MQNB结合似乎是不可逆转的，但我们的发现表明拮抗剂的结合非常迅速，解离远非可以忽略不计。然而，解离的配体很有可能重新结合到游离受体位点，而不是逃逸到微循环中。我们推断，注射微量[11 C]MQNB后获得的正电子发射断层扫描图像比受体密度或亲和力更能代表血流。我们还建议了一种简化的方案，包括示踪剂注射[11 C]MQNB和第二次注射过量的冷MQNB，这足以测量人体中的B“max和Kd。
The in vivo quantification of myocardial muscarinic receptors has been obtained in six closed-chest dogs by using positron emission tomography. The dogs were injected with a trace amount of 11C-labeled methylquinuclidinyl benzilate (MQNB), a nonmetabolized antagonist of the muscarinic receptor. This was followed 30 minutes later by an injection of an excess of unlabeled MQNB (displacement experiment). Two additional injections of unlabeled MQNB with [11C]MQNB (coinjection experiment) and without [11C]MQNB (second displacement experiment) were administered after 70 and 120 minutes, respectively, This protocol allowed a separate evaluation of the quantity of available receptors (B''max) as well as the association and dissociation rate constants (k+1 and k-1) in each dog. The parameters were calculated by using a nonlinear mathematical model in regions of interest over the left ventricle and the interventricular septum. The average value of B''max was 42.+-.11 pmol/ml tissue, the rate constants k+1, k-1, and Kd were 0.6.+-.0.1 ml .cntdot. pmol-1 .cntdot. min-1, 0.27.+-. 0.03 ml .cntdot. pmol-1 .cntdot. min -1, and 0.49.+-.0.14 pmol .cntdot. ml-1, respectively, taking into account the MQNB reaction volume estimated to 0.15 ml/ml tissue. Although [11C]MQNB binding would appear ireeversible our findings indicate that the association of the antagonist is very rapid and that the dissociation is far from negligible. The dissociated ligand, however, has a high probability of rebinding to a free receptor site instead of escaping into the microcirculation. We deduce that the positron emission tomographic images obtained after injecting a trace amount of [11C]MQNB are more representative of blood flow than of receptor density or affinity. We also suggest a simplified protocol consisting of a tracer injection of [11C]MQNB and a second injection of an excess of cold MQNB, which is sufficient to measure B''max and Kd in humans.