Laboratory for Radiopharmacy, Faculty of Pharmaceutical Sciences, K.U. Leuven, Leuven, Belgium.
J Nucl Med. 2010 Oct;51(10):1584-91. doi: 10.2967/jnumed.110.077040. Epub 2010 Sep 16.
Phosphodiesterases are enzymes that inactivate the intracellular second messengers 3',5'-cyclic adenosine-monophosphate and/or cyclic guanosine-monophosphate. Of all 11 known phosphodiesterase families, phosphodiesterase-10A (PDE10A) has the most restricted distribution, with high expression in the striatum. PDE10A inhibitors are pursued as drugs for treatment of neuropsychiatric disorders. We have synthesized and evaluated (18)F-JNJ41510417 as a selective and high-affinity radioligand for in vivo brain imaging of PDE10A using PET.
The biodistribution of (18)F-JNJ41510417 was evaluated in rats. Rat plasma and perfused brain homogenates were analyzed by high-performance liquid chromatography to quantify radiometabolites. Dynamic small-animal PET was performed in rats and in wild-type and PDE10A knock-out mice and compared with ex vivo autoradiography. Blocking and displacement experiments were performed using the nonradioactive analog and other selective PDE10A inhibitors.
Tissue distribution studies showed predominant hepatobiliary excretion, sufficient brain uptake (0.56 ± 0.00 percentage injected dose at 2 min after tracer injection), and continuous accumulation of the tracer in the striatum over time; rapid washout of nonspecific binding from other brain regions was observed. Polar radiometabolites were detected in plasma and brain tissue. Dynamic small-animal PET showed continuous tracer accumulation in the striatum, with rapid decline in the cortex and cerebellum. Pretreatment and chase experiments with PDE10A inhibitors showed that the tracer binding to PDE10A was specific and reversible. Imaging in PDE10A knock-out and wild-type mice further confirmed that binding in the striatum was specific for PDE10A.
Experiments in rats and PDE10A knock-out mice indicate that (18)F-JNJ41510417 binds specifically and reversibly to PDE10A in the striatum, suggesting that this new fluorinated quinoline derivative is a promising candidate for in vivo imaging of PDE10A using PET.
评估 18F-JNJ41510417 作为 PDE10A 用于正电子发射断层扫描（PET）体内脑成像的选择性和高亲和力放射性配体的可行性。
在大鼠中评估 18F-JNJ41510417 的生物分布。通过高效液相色谱法分析大鼠血浆和灌注脑匀浆，以定量放射性代谢产物。在大鼠和 PDE10A 敲除小鼠中进行小动物动态 PET 扫描，并与离体放射性自显影进行比较。使用非放射性类似物和其他选择性 PDE10A 抑制剂进行阻断和置换实验。
组织分布研究显示主要经肝胆排泄，脑摄取充足（示踪剂注射后 2 分钟时为 0.56±0.00%注射剂量），随时间推移在纹状体中持续积累示踪剂；观察到其他脑区的非特异性结合快速洗脱。在血浆和脑组织中检测到极性放射性代谢产物。小动物动态 PET 显示纹状体中示踪剂持续积累，皮质和小脑迅速下降。PDE10A 抑制剂的预处理和追赶实验表明，示踪剂与 PDE10A 的结合是特异性和可逆的。在 PDE10A 敲除和野生型小鼠中的成像进一步证实了纹状体中的结合是特异性的 PDE10A。
在大鼠和 PDE10A 敲除小鼠中的实验表明，18F-JNJ41510417 特异性和可逆地结合到纹状体中的 PDE10A，表明这种新的氟代喹啉衍生物是使用 PET 进行 PDE10A 体内成像的有前途的候选物。
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