Léger G, Gjedde A, Kuwabara H, Guttman M, Cumming P
McConnell Brain Imaging Centre, Montreal Neurological Institute, Canada.
Synapse. 1998 Dec;30(4):351-61. doi: 10.1002/(SICI)1098-2396(199812)30:4<351::AID-SYN2>3.0.CO;2-2.
The efficacy of levo-DOPA in the treatment of Parkinson's disease is potentiated by blockade of its peripheral metabolism with inhibitors of catechol-O-methyltransferase (COMT). Some COMT inhibitors may act entirely in the periphery (nitecapone, OR-462), while others may also have some activity in brain (entacapone, OR-611). We used positron emission tomography (PET) to test the effects of these two COMT inhibitors on the plasma kinetics and brain metabolism of the levo-DOPA analog 6-[18F]fluoro-L-dopa (FDOPA) in cynomolgus monkeys, employing a compartmental model for the assay of DOPA decarboxylase activity in living brain. Four monkeys each underwent two PET scans in the baseline condition, one PET scan after treatment with OR-462 (15 mg/kg, i.v.), and one PET scan after treatment with OR-611 (15 mg/kg, i.v.). Pharmacokinetic analysis of FDOPA metabolism in plasma indicated that these compounds blocked peripheral COMT activity by 80% for at least 60 minutes. Both COMT inhibitors increased the net availability of FDOPA in circulation, and increased the ratio of the radioactivity concentrations in striatum and occipital cortex, suggesting that [18F]fluorodopamine synthesis in striatum was potentiated. However, OR-611 treatment reduced the unidirectional (K1D) and net (Ki) blood-brain clearances of FDOPA, and also inhibited the rate of decarboxylation (k3D) of FDOPA in striatum. These observations suggest that high doses of OR-611 may partially antagonize the cerebral utilization of levo-DOPA. We used the present data to test the sensitivity of the compartmental model to the physiological constraint that the blood-brain permeabilities of the O-methylated plasma metabolite and FDOPA have a fixed ratio. In the groups with COMT inhibition, the estimates of k3D were insensitive to the magnitude of the permeability ratio. In the control group, the estimate of k3D increased by 40% as the magnitude of the constrained permeability ratio increased in the range of published estimates.
左旋多巴治疗帕金森病的疗效可通过使用儿茶酚-O-甲基转移酶（COMT）抑制剂阻断其外周代谢来增强。一些COMT抑制剂可能完全在外周起作用（硝替卡朋、OR-462），而其他一些抑制剂在脑内也可能有一定活性（恩他卡朋、OR-611）。我们使用正电子发射断层扫描（PET）来测试这两种COMT抑制剂对食蟹猴体内左旋多巴类似物6-[¹⁸F]氟-L-多巴（FDOPA）的血浆动力学和脑代谢的影响，采用房室模型测定活体脑内多巴脱羧酶活性。4只猴子在基线条件下各进行两次PET扫描，静脉注射OR-462（15mg/kg）后进行一次PET扫描，静脉注射OR-611（15mg/kg）后进行一次PET扫描。血浆中FDOPA代谢的药代动力学分析表明，这些化合物可使外周COMT活性至少60分钟内降低80%。两种COMT抑制剂均增加了循环中FDOPA的净利用率，并提高了纹状体和枕叶皮质放射性浓度的比值，提示纹状体内[¹⁸F]氟多巴胺的合成增强。然而，OR-治疗降低了FDOPA的单向（K1D）和净（Ki）血脑清除率，也抑制了纹状体内FDOPA的脱羧速率（k3D）。这些观察结果表明，高剂量的OR-611可能部分拮抗左旋多巴的脑内利用。我们利用目前的数据测试房室模型对O-甲基化血浆代谢物和FDOPA的血脑通透性具有固定比值这一生理限制的敏感性。在COMT抑制组中，k3D估计值对通透性比值的大小不敏感。在对照组中，随着受限通透性比值大小在已发表估计范围内增加，k3D估计值增加了40%。
