Cumming P, Gjedde A
McConnell Brain Imaging Centre, Montreal Neurological Institute, PQ Canada.
Synapse. 1998 May;29(1):37-61. doi: 10.1002/(SICI)1098-2396(199805)29:1<37::AID-SYN4>3.0.CO;2-C.
The trapping of decarboxylation products of radiolabelled dopa analogs in living human brain occurs as a function of the activity of dopa decarboxylase. This enzyme is now understood to regulate, with tyrosine hydroxylase, cerebral dopamine synthesis. Influx into brain of dopa decarboxylase substrates such as 6-[18F]fluorodopa and beta-[11C]dopa measured by positron emission tomography can be analyzed by solution of linear differential equations, assuming irreversible trapping of the decarboxylated products in brain. The isolation of specific physiological steps in the pathway for catecholamine synthesis requires compartmental modelling of the observed dynamic time-activity curves in plasma and in brain. The several approaches to the compartmental modelling of the kinetics of labelled substrates of dopa decarboxylase are now systematically and critically reviewed. Labelled catechols are extensively metabolized by hepatic catechol-O-methyltransferase yielding brain-penetrating metabolites. The assumption of a fixed blood-brain permeability ratio for O-methyl-6-[18F]fluorodopa or O-methyl-beta-[11C]dopa to the parent compounds eliminates several parameters from compartmental models. However, catechol-O-methyltransferase activity within brain remains a possible factor in underestimation of cerebral dopa decarboxylase activity. The O-methylation of labelled catechols is blocked with specific enzyme inhibitors, but dopa decarboxylase substrates derived from m-tyrosine may supplant the catechol tracers. The elimination from brain of decarboxylated tracer metabolites can be neglected without great prejudice to the estimation of dopa decarboxylase activity when tracer circulation is less than 60 minutes. However, elimination of dopamine metabolites from brain occurs at a rate close to that observed previously for metabolites of glucose labelled in the 6-position. This phenomenon can cause systematic underestimation of the rate of dopa decarboxylation in brain. The spillover of radioactivity due to the limited spatial resolution of tomographs also results in underestimation of dopa decarboxylase activity, but correction for partial volume effects is now possible. Estimates of dopa decarboxylase activity in human brain are increased several-fold by this correction. Abnormally low influx of dopa decarboxylase tracers in the basal ganglia is characteristic of Parkinson's disease and other movement disorders. Consistent with postmortem results, the impaired retention of labelled dopa is more pronounced in the putamen than in the caudate nucleus of patients with Parkinson's disease; this heterogeneity persists after correction for spillover. Current in vivo assays of dopa decarboxylase activity fail to discriminate clinically distinct stages in the progression of Parkinson's disease and are, by themselves, insufficient for differential diagnosis of Parkinson's disease and other subcortical movement disorders. However, potential new avenues for therapeutics can be tested by quantifying the rate of metabolism of exogenous dopa in living human brain.
放射性标记多巴类似物的脱羧产物在活体人脑中的滞留是多巴脱羧酶活性的函数。现在已知该酶与酪氨酸羟化酶一起调节脑内多巴胺的合成。通过正电子发射断层扫描测量的多巴脱羧酶底物（如6-[18F]氟多巴和β-[11C]多巴）进入脑内的情况，可以通过线性微分方程的解进行分析，假设脱羧产物在脑内不可逆地滞留。儿茶酚胺合成途径中特定生理步骤的分离需要对血浆和脑内观察到的动态时间-活性曲线进行房室建模。现在系统地、批判性地回顾了几种对多巴脱羧酶标记底物动力学进行房室建模的方法。标记的儿茶酚被肝脏儿茶酚-O-甲基转移酶广泛代谢，产生可穿透脑的代谢产物。假设O-甲基-6-[18F]氟多巴或O-甲基-β-[11C]多巴与母体化合物的血脑渗透率固定比值，可以从房室模型中消除几个参数。然而，脑内儿茶酚-O-甲基转移酶活性仍然可能是低估脑内多巴脱羧酶活性的一个因素。标记儿茶酚的O-甲基化被特定的酶抑制剂阻断，但源自间酪氨酸的多巴脱羧酶底物可能会取代儿茶酚示踪剂。当示踪剂循环时间小于60分钟时，脱羧示踪剂代谢产物从脑内的消除可以忽略不计，而不会对多巴脱羧酶活性的估计产生太大影响。然而，多巴胺代谢产物从脑内的消除速度与先前观察到的6位标记葡萄糖代谢产物的速度相近。这种现象可能导致对脑内多巴脱羧化速度的系统性低估。由于断层扫描仪有限的空间分辨率导致的放射性溢出也会导致多巴脱羧酶活性的低估，但现在可以对部分容积效应进行校正。通过这种校正，人脑中多巴脱羧酶活性的估计值增加了几倍。基底神经节中多巴脱羧酶示踪剂的异常低流入是帕金森病和其他运动障碍的特征。与死后结果一致，帕金森病患者壳核中标记多巴的保留受损比尾状核更明显；校正溢出后这种异质性仍然存在。目前体内多巴脱羧酶活性测定无法区分帕金森病进展中临床上不同的阶段，其本身也不足以对帕金森病和其他皮质下运动障碍进行鉴别诊断。然而，通过量化活体人脑中内源性多巴的代谢速度，可以测试潜在的新治疗途径。
