Morris E D, Babich J W, Alpert N M, Bonab A A, Livni E, Weise S, Hsu H, Christian B T, Madras B K, Fischman A J
Department of Radiology, Massachusetts General Hospital, Boston 02114, USA.
Synapse. 1996 Nov;24(3):262-72. doi: 10.1002/(SICI)1098-2396(199611)24:3<262::AID-SYN9>3.0.CO;2-C.
Idiopathic Parkinson's disease (PD) is characterized by loss of dopaminergic terminals in the basal ganglia. The cocaine analog, CFT (WIN 35,428), has been shown to bind selectively to the pre-synaptic dopamine transporters and thus represents an important probe for monitoring disease progression. In this study, we evaluated [11C] labeled CFT as a PET ligand for the quantitative in vivo assay of dopamine transporter density in three normal rhesus monkeys (Macaca mulatta). One of the animals was studied after treatment with the neurotoxin, MPTP. Simulation studies demonstrated that a three injection protocol is necessary for quantitation of dopamine transporter density. The protocol consists of an initial high specific activity injection, a low specific activity "displacement dose" at 30 min, and a final high specific activity injection at approximately 90 min. Dynamic PET imaging and arterial blood sampling were started immediately before the first injection and continued for 2 h. Blood data were corrected for [11C] labeled CFT metabolites. Compartmental models describing the dynamics of labeled and the unlabeled ligand explicitly were fitted to the PET and metabolite corrected blood data. Prior to MPTP treatment, modeling of the striatal data required a saturable receptor term and yielded mean estimates of: B'max = 113 pmol/g and KD = 33 nm (n = 3). These values for B'max are in reasonable agreement with published values for [3H] CFT binding in vitro. After multiple treatments with MPTP (0.6 mg/kg x 3), B'max in one of the animals was reduced from 122 to 10.2 pmol/g. KD was relatively unaffected by MPTP treatment. These data provide additional basis for the use of [11C] CFT in monitoring the progression of Parkinson's disease and other conditions that are associated with the loss of dopaminergic nerve terminals.
特发性帕金森病（PD）的特征是基底神经节中多巴胺能终末的丧失。可卡因类似物CFT（WIN 35,428）已被证明能选择性地结合突触前多巴胺转运体，因此是监测疾病进展的重要探针。在本研究中，我们评估了[11C]标记的CFT作为PET配体，用于对三只正常恒河猴（猕猴）体内多巴胺转运体密度进行定量分析。其中一只动物在接受神经毒素MPTP治疗后进行了研究。模拟研究表明，采用三次注射方案对于定量多巴胺转运体密度是必要的。该方案包括一次初始的高比活度注射、30分钟时的低比活度“置换剂量”以及大约90分钟时的最后一次高比活度注射。在第一次注射前立即开始动态PET成像和动脉血采样，并持续2小时。对血液数据进行了[11C]标记的CFT代谢物校正。将明确描述标记和未标记配体动力学的房室模型拟合到PET和代谢物校正后的血液数据。在MPTP治疗前，对纹状体数据进行建模需要一个可饱和的受体项，得出的平均估计值为：B'max = 113 pmol/g，KD = 33 nm（n = 3）。这些B'max值与已发表的[3H] CFT体外结合值合理一致。在用MPTP（0.6 mg/kg×3）多次治疗后，其中一只动物的B'max从122降至10.2 pmol/g。KD相对不受MPTP治疗的影响。这些数据为使用[11C] CFT监测帕金森病及其他与多巴胺能神经终末丧失相关疾病的进展提供了更多依据。
