Cumming Paul, Maschauer Simone, Riss Patrick J, Tschammer Nuska, Fehler Stefanie K, Heinrich Markus R, Kuwert Torsten, Prante Olaf
Department of Nuclear Medicine, Laboratory of Molecular Imaging and Radiochemistry, Friedrich Alexander University, Erlangen, Germany.
Department of Chemistry, Universitetet i Oslo & Norsk Medisinisk Syklotronsenter AS, Oslo, Norway.
J Cereb Blood Flow Metab. 2014 Jul;34(7):1148-56. doi: 10.1038/jcbfm.2014.63. Epub 2014 Apr 9.
To date there is no validated, (18)F-labeled dopamine transporter (DAT) radiotracer with a rapid kinetic profile suitable for preclinical small-animal positron emission tomography (PET) studies in rodent models of human basal ganglia disease. Herein we report radiosynthesis and validation of the phenyltropane (18)F-FP-CMT. Dynamic PET recordings were obtained for (18)F-FP-CMT in six untreated rats, and six rats pretreated with the high-affinity DAT ligand GBR 12909; mean parametric maps of binding potential (BPND) relative to the cerebellum reference region, and maps of total distribution volume (VT) relative to the metabolite-corrected arterial input were produced. (18)F-FP-CMT BPND maps showed peak values of ∼4 in the striatum, versus ∼0.4 in the vicinity of the substantia nigra. Successive truncation of the PET recordings indicated that stable BPND estimates could be obtained with recordings lasting only 45 minutes, reflecting rapid kinetics of (18)F-FP-CMT. Pretreatment with GBR 12909 reduced the striatal binding by 72% to 76%. High-performance liquid chromatography analysis revealed rapid metabolism of (18)F-FP-CMT to a single, non-brain penetrant hydrophilic metabolite. Total distribution of volume calculated relative to the metabolite-corrected arterial input was 4.4 mL/g in the cerebellum. The pharmacological selectivity of (18)F-FP-CMT, rapid kinetic profile, and lack of problematic metabolites constitute optimal properties for quantitation of DAT in rat, and may also predict applicability in human PET studies.
迄今为止，尚无经过验证的、具有快速动力学特征的（18）F标记多巴胺转运体（DAT）放射性示踪剂，适用于人类基底神经节疾病啮齿动物模型的临床前小动物正电子发射断层扫描（PET）研究。在此，我们报告了苯托烷（18）F-FP-CMT的放射性合成及验证。对6只未经处理的大鼠和6只预先用高亲和力DAT配体GBR 12909处理的大鼠进行了（18）F-FP-CMT的动态PET记录；生成了相对于小脑参考区域的结合潜能（BPND）平均参数图，以及相对于代谢物校正动脉输入的总分布容积（VT）图。（18）F-FP-CMT的BPND图显示纹状体峰值约为4，而黑质附近约为0.4。PET记录的连续截断表明，仅持续45分钟的记录就能获得稳定的BPND估计值，这反映了（18）F-FP-CMT的快速动力学。用GBR 12909预处理可使纹状体结合减少72%至76%。高效液相色谱分析显示（18）F-FP-CMT迅速代谢为单一的、非脑渗透性亲水性代谢物。相对于代谢物校正动脉输入计算的小脑总分布容积为4.4 mL/g。（18）F-FP-CMT的药理选择性、快速动力学特征以及不存在有问题的代谢物构成了大鼠DAT定量的最佳特性，也可能预示其在人类PET研究中的适用性。
