Psylla M, Günther I, Antonini A, Vontobel P, Reist H W, Zollinger A, Leenders K L
PET Department, Paul Scherrer Institute, Switzerland.
Brain Res. 1997 Aug 29;767(1):45-54. doi: 10.1016/s0006-8993(97)00552-0.
FDOPA/PET scans were performed in one rhesus monkey to study the influence of three catechol-O-methyltransferase (COMT) inhibitors (CGP 28014, OR-611 and Ro 40-7592) on FDOPA pharmacokinetics. COMT inhibitors were administered in combination with carbidopa, a peripherally acting inhibitor of the aromatic amino acid decarboxylase (AAAD). FDOPA was administered intravenously and its metabolic fate in plasma was determined using an HPLC system with an on-line gamma-gamma coincidence detector. Cerebral tracer uptake was assessed in the striatum and in a non-dopaminergic brain region (occipital cortex). In the periphery, the pharmacokinetic efficiency of FDOPA was increased due to the combined inhibition of COMT and AAAD activity. All three COMT inhibitors reduced the FDOPA methylation rate constant in plasma, with complete suppression obtained in the case of Ro 40-7592. In the brain, specific 18F radioactivity (striatal minus brain reference radioactivity) increased as a result of the increase in FDOPA plasma availability following the administration of COMT and AAAD inhibitors. We established a significant linear correlation between striatal radioactivity and FDOPA plasma levels (r = 0.924 +/- 0.048, P < 0.0001 for total striatal and r = 0.948 +/- 0.054, P < 0.0001 for specific striatal radioactivity). Using plasma FDOPA radioactivity as input, we found that the striatal FDOPA uptake rate constant KiFD was not changed by any of the inhibitors. Thus, the enhancement of striatal radioactivity after application of enzyme inhibitors is a consequence of the increase in plasma FDOPA that becomes available for conversion to fluorodopamine in the striatal dopaminergic nerve terminals. By contrast, using the radioactivity in a non-dopaminergic region (cortex) as input, we found that the striatal FDOPA uptake rate constant Ki(ref) was significantly (P < 0.0001) increased following pretreatment with COMT inhibitors. Our analysis demonstrated that Ki(ref) and the 3-OMFD contribution to the cerebral radioactivity were inversely correlated.
对一只恒河猴进行了氟代多巴（FDOPA）/正电子发射断层扫描（PET），以研究三种儿茶酚-O-甲基转移酶（COMT）抑制剂（CGP 28014、OR-611和Ro 40-7592）对FDOPA药代动力学的影响。COMT抑制剂与外周作用的芳香族氨基酸脱羧酶（AAAD）抑制剂卡比多巴联合给药。静脉注射FDOPA，并使用带有在线γ-γ符合探测器的高效液相色谱系统测定其在血浆中的代谢命运。在纹状体和非多巴胺能脑区（枕叶皮质）评估脑内示踪剂摄取。在周围组织中，由于COMT和AAAD活性的联合抑制，FDOPA的药代动力学效率提高。所有三种COMT抑制剂均降低了血浆中FDOPA的甲基化速率常数，Ro 40-7592可完全抑制该常数。在脑内，给予COMT和AAAD抑制剂后，由于FDOPA血浆可用性增加，特定的18F放射性（纹状体减去脑参考放射性）增加。我们建立了纹状体放射性与FDOPA血浆水平之间的显著线性相关性（总纹状体r = 0.924±0.048，P < 0.0001；特定纹状体放射性r = 0.948±0.054，P < 0.0001）。以血浆FDOPA放射性作为输入，我们发现任何一种抑制剂均未改变纹状体FDOPA摄取速率常数KiFD。因此，应用酶抑制剂后纹状体放射性增强是血浆FDOPA增加的结果，增加的FDOPA可在纹状体多巴胺能神经末梢转化为氟多巴胺。相比之下，以非多巴胺能区域（皮质）的放射性作为输入，我们发现用COMT抑制剂预处理后，纹状体FDOPA摄取速率常数Ki(ref)显著增加（P < 0.0001）。我们的分析表明，Ki(ref)与3-OMFD对脑放射性的贡献呈负相关。
