DRUG RECEPTORS IN VIVO

在可卡因成像领域已经取得了相当大的进展 活体动物体内的受体。我们的第一个努力是利用一种已知的 抗抑郁药诺米芬辛。体内结合的详细研究 该化合物的特征表明它定位于多巴胺。 转运蛋白非常有效，但特异性到非特异性较低 结合率。正因为如此，我们着手开发更高效的 结合配体。 我们实验室之前的研究表明，可卡因类似物， Win-35,065-2和Win-35,428是较好的多巴胺配体 转运体中特异性与非特异性结合率较高 在活体内获得。最近，我们使用了Win-35,428 广泛的研究，最终表明这种化合物定位于 对大鼠纹状体可卡因受体/多巴胺转运体的影响。我们现在在 利用这种化合物以其正电子发射形式携带的过程 体内多巴胺转运体的OUT PET扫描研究。 活体标记技术的一个重要用途是检查 不同药物对受体在体内的占有率。因为 使用Win-35,428的体内标记模型的可用性，我们能够 为了检测马吲哚对可卡因受体的相对占有率， GBR-12,909和可卡因。我们清楚地表明可卡因进入大脑 比马吲哚更快地占据可卡因受体 GBR-12,909。众所周知，滥用药物的责任更大， 进入大脑并迅速占据感受器。因此，这个模型将是 有助于定量评估药物进入大脑的速度和 占领受体；这将有助于在 了解此因素以进行滥用责任评估。

Considerable progress has been made in the area of imaging cocaine receptors in living animals. Our first efforts involved utilizing a known antidepressant drug, nomifensine. A detailed study of the in vivo binding characteristics of this compound revealed that it localized to dopamine transporters quite effectively but with a low specific to non-specific binding ratio. Because of this, we set out to develop more efficient binding ligands. Studies from our laboratory previously showed that cocaine analogs, WIN-35,065-2 and WIN-35,428 were better ligands for the dopamine transporter in that higher specific to non-specific binding ratios were obtained in vivo. More recently, we utilized WIN-35,428 in a more extensive study which conclusively showed that this compound localized to cocaine receptors/dopamine transporters in rat striatum. We are in the process of utilizing this compound in its positron emitting form to carry out PET scanning studies of dopamine transporters in vivo. One important use of in vivo labelling techniques is to examine the rate of occupancy of receptors in vivo by various drugs. Because of the availability of our in vivo labeling model using WIN-35,428, we were able to examine the relative rate of occupancy of cocaine receptor by mazindol, GBR-12,909 and cocaine. We clearly showed that cocaine enters the brain and occupies cocaine receptors much more rapidly than mazindol or GBR-12,909. It is known that abuse liability is greater for drugs that enter the brain and occupy receptors rapidly. Thus, this model will be useful in quantitatively assessing how rapidly drugs enter the brain and occupy receptors; this will be helpful in contributing quantitative knowledge of this factor for abuse liability assessment.