Endres Christopher J, DeJesus Onofre T, Uno Hideo, Doudet Doris J, Nickles Jerome R, Holden James E
Department of Medical Physics, University of Wisconsin Medical School, Madison, WI 53706, USA.
Front Biosci. 2004 Jan 1;9:505-12. doi: 10.2741/1224.
At least two rates of dopamine turnover have been demonstrated in vivo, including a slow turnover rate that is associated with synaptic vesicles, and a faster rate that leads to rapid production of dopamine metabolites. Similarly, [18F]6-fluorodopamine (FDA), the decarboxylation product of the PET tracer [18F]6-fluoro-L-DOPA (FDOPA), may have multiple turnover rates which could substantially affect the interpretation of FDOPA uptake. To better characterize FDA turnover in vivo, we measured the formation of FDOPA metabolites in primate brain following bolus FDOPA injection with carbidopa pretreatment. FDOPA was allowed to circulate for either 30 minutes or 90 minutes, prior to removal of brain samples. The primary metabolites in striatum were [18F]6-fluoro-3-methyl-L-DOPA (3-OMFD), FDA, [18F]6-fluoro- L-3,4-dihydroxyphenylacetic acid (FDOPAC), and [18F]6-fluorohomovanillic acid (FHVA). The percentages of total radioactivity in striatum at 30 minutes and 90 minutes were: FDOPA(5%, 2%), FDA (39%, 23%), FDOPAC (12%, 3%), FHVA (14%, 34%), and 3-OMFD (29%, 39%). In cortex and cerebellum most of the activity (73%, 80%) was 3-OMFD. These data were compared against the metabolite profiles predicted by two compartmental models of FDOPA metabolism. A model that assumes only a single slow rate of FDA turnover predicted much lower concentrations of FDA metabolites (FDOPAC, FHVA) in striatum than were found in the brain assay, while a model that includes both slow and fast FDA turnover was in much better agreement. These findings extend and confirm previous observations of FDOPA metabolites. The implications for the interpretation of FDOPA PET, particularly in terms of the availability of dopamine synthesized from therapeutic L-DOPA, are discussed.
体内已证实多巴胺周转至少有两种速率，包括与突触小泡相关的缓慢周转速率，以及导致多巴胺代谢产物快速产生的较快速率。同样，PET示踪剂[18F]6-氟-L-多巴（FDOPA）的脱羧产物[18F]6-氟多巴胺（FDA）可能有多种周转速率，这可能会严重影响对FDOPA摄取的解释。为了更好地表征体内FDA的周转情况，我们在预先用卡比多巴预处理后，静脉注射FDOPA推注剂量后，测量了灵长类动物大脑中FDOPA代谢产物的形成。在取出脑样本之前，让FDOPA循环30分钟或90分钟。纹状体中的主要代谢产物是[18F]6-氟-3-甲基-L-多巴（3-OMFD）、FDA、[18F]6-氟-L-3,4-二羟基苯乙酸（FDOPAC）和[18F]6-氟高香草酸（FHVA）。30分钟和90分钟时纹状体中总放射性的百分比分别为：FDOPA（5%，2%）、FDA（39%，23%）、FDOPAC（12%，3%）、FHVA（14%，34%）和3-OMFD（29%，39%）。在皮质和小脑中，大部分活性（73%，80%）是3-OMFD。将这些数据与FDOPA代谢的两室模型预测的代谢产物谱进行了比较。一个仅假设FDA周转单一缓慢速率的模型预测纹状体中FDA代谢产物（FDOPAC、FHVA）的浓度比在脑实验中发现的要低得多，而一个包括FDA缓慢和快速周转的模型则更吻合。这些发现扩展并证实了先前关于FDOPA代谢产物的观察结果。讨论了其对FDOPA PET解释的影响，特别是在由治疗性L-DOPA合成的多巴胺可用性方面。
