Scheffel U, Steinert C, Kim S E, Ehlers M D, Boja J W, Kuhar M J
Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Synapse. 1996 Jun;23(2):61-9. doi: 10.1002/(SICI)1098-2396(199606)23:2<61::AID-SYN1>3.0.CO;2-E.
[11C]WIN 35,428 (also designated [11C]CFT) is now being used in several positron emission tomography (PET) centers to image dopamine (DA) transporter sites in the mammalian brain. Whether and to what extent in vivo WIN 35,428 binding is influenced by intra- and extrasynaptic dopamine levels are largely unknown. The purpose of the present study was to evaluate the effects of various drugs, known to affect DA levels and release, on the binding of [3H]WIN 35,428 to central DA transporters in the mouse brain. D-Amphetamine, which releases DA from neurons and blocks the DA transporter directly, inhibited striatal [3H]WIN 35,428 binding in dose-dependent manner. Similarly, alpha-methyl-DL-p-tyrosine, an inhibitor of tyrosine hydroxylase, blocked [3H]WIN 35,428 binding, possibly via competitive inhibition by the metabolite p-hydroxyamphetamine. Specific binding of [3H]WIN 35,428 was insensitive to changes in synaptic DA levels caused by pretreatment of the animals with high doses of D2 receptor agonists (apomorphine, bromocriptine), antagonists (haloperidol) or the inhibitor of dopaminergic neuron firing gamma-butyrolactone (GBL). High doses (> 50 mg/kg) of L-DOPA (in combination with benserazide), however, reduced [3H]WIN 35,428 binding significantly, yet for a relatively short time (approximately 2.5 h). Chronic treatment with L-deprenyl elicited no changes in in vivo [3H]WIN 35,428 accumulation in the striatum. Neurotoxic damage of DA neurons caused by administration of high doses of amphetamine was detected in the striatum by a significant reduction in [3H]WIN 35,428 binding 7 days after cessation of amphetamine treatment. Thus, [3H]WIN 35,428 binding was only affected by neurotoxic loss of neurons, by administration of uptake inhibitors, or by some treatments which significantly elevate DA levels. Compounds which inhibit DA release or deplete DA acutely do not increase [3H]WIN 35,428 binding, suggesting that normal or "resting" levels of DA are not sufficient to alter [3H]WIN 35,428 binding in vivo. These findings are important for our understanding of the function and regulation of the DA transporter, as well as the in vivo binding of the radioligand [3H/11 C]WIN 35,428. Moreover, they will be important for the interpretation of PET studies in which [11C]WIN 35,428 is used to assess the integrity of dopaminergic neurons.
[11C]WIN 35,428（也被指定为[11C]CFT）目前正在多个正电子发射断层扫描（PET）中心用于成像哺乳动物大脑中的多巴胺（DA）转运体位点。体内WIN 35,428结合是否以及在何种程度上受突触内和突触外多巴胺水平的影响在很大程度上尚不清楚。本研究的目的是评估各种已知会影响DA水平和释放的药物对[3H]WIN 35,428与小鼠大脑中中枢DA转运体结合的影响。D-苯丙胺从神经元释放DA并直接阻断DA转运体，以剂量依赖性方式抑制纹状体[3H]WIN 35,428结合。同样，酪氨酸羟化酶抑制剂α-甲基-DL-对酪氨酸阻断[3H]WIN 35,428结合，可能是通过代谢物对羟基苯丙胺的竞争性抑制。[3H]WIN 35,428的特异性结合对高剂量D2受体激动剂（阿扑吗啡、溴隐亭）、拮抗剂（氟哌啶醇）或多巴胺能神经元放电抑制剂γ-丁内酯（GBL）预处理引起的突触DA水平变化不敏感。然而，高剂量（>50mg/kg）的左旋多巴（与苄丝肼联合使用）显著降低了[3H]WIN 35,428结合，但持续时间相对较短（约2.5小时）。长期用L-司来吉兰治疗未引起纹状体中体内[3H]WIN 35,428积累的变化。在苯丙胺治疗停止7天后，通过[3H]WIN 35,428结合的显著降低在纹状体中检测到高剂量苯丙胺给药引起的DA神经元神经毒性损伤。因此，[3H]WIN 35,428结合仅受神经元的神经毒性损失、摄取抑制剂的给药或一些显著升高DA水平的治疗的影响。急性抑制DA释放或消耗DA的化合物不会增加[3H]WIN 35,428结合，这表明正常或“静息”水平的DA不足以改变体内[3H]WIN 35,428结合。这些发现对于我们理解DA转运体的功能和调节以及放射性配体[3H/11C]WIN 35,428的体内结合很重要。此外，它们对于解释使用[11C]WIN 35,428评估多巴胺能神经元完整性的PET研究也很重要。
