Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
J Cereb Blood Flow Metab. 2012 Apr;32(4):685-95. doi: 10.1038/jcbfm.2011.172. Epub 2011 Dec 14.
Assessment of serotonin release in the living brain with positron emission tomography (PET) may have been hampered by the lack of suitable radioligands. We previously reported that fenfluramine caused a dose-dependent reduction in specific binding in monkeys using a classical displacement paradigm with bolus administration of [(11)C]AZ10419369. The aim of this study was to confirm our previous findings using an equilibrium approach in monkey. A total of 24 PET measurements were conducted using a bolus infusion protocol of [(11)C]AZ10419369 in three cynomolgus monkeys. Initial PET measurements were performed to assess suitable K(bol) values. The fenfluramine effect on [(11)C]AZ10419369 binding was evaluated in a displacement and pretreatment paradigm. The effect of fenfluramine on [(11)C]AZ10419369 binding potential (BP(ND)) was dose-dependent in the displacement paradigm and confirmed in the pretreatment paradigm. After pretreatment administration of fenfluramine (5.0 mg/kg), the mean BP(ND) of the occipital cortex decreased by 39%, from 1.38±0.04 to 0.84±0.09. This study confirms that the new 5-HT(1B) receptor radioligand [(11)C]AZ10419369 is sensitive to fenfluramine-induced changes in endogenous serotonin levels in vivo. The more advanced methodology is suitable for exploring the sensitivity limit to serotonin release as measured using [(11)C]AZ10419369 and PET.
使用正电子发射断层扫描（PET）评估活脑中的血清素释放可能因缺乏合适的放射性配体而受到阻碍。我们之前报道过，使用经典的脉冲式给药取代研究范式，在猴子中，芬氟拉明会导致（11C）AZ10419369 的特异性结合呈剂量依赖性减少。本研究旨在使用猴子的平衡方法来证实我们之前的发现。在三只食蟹猴中，通过（11C）AZ10419369 的脉冲输注方案进行了总共 24 次 PET 测量。最初的 PET 测量是为了评估合适的 Kbol 值。使用置换和预处理范式评估了芬氟拉明对（11C）AZ10419369 结合的影响。在置换范式中，芬氟拉明对（11C）AZ10419369 结合潜能（BP（ND））的影响呈剂量依赖性，并在预处理范式中得到了证实。在给予芬氟拉明（5.0mg/kg）预处理后，枕叶皮质的平均 BP（ND）下降了 39%，从 1.38±0.04 降至 0.84±0.09。本研究证实，新型 5-HT1B 受体放射性配体（11C）AZ10419369 对体内内源性血清素水平的芬氟拉明诱导变化敏感。更先进的方法学适合探索使用（11C）AZ10419369 和 PET 测量的血清素释放的敏感性极限。
