Passchier J, van Waarde A, Pieterman R M, Willemsen A T, Vaalburg W
PET Center, Groningen University Hospital, The Netherlands.
Psychopharmacology (Berl). 2001 May;155(2):193-7. doi: 10.1007/s002130100688.
There is an increased interest in measuring the interaction of new or established drugs with their targets, in order to gain a better understanding of their mechanisms of action. PET can provide this information if an appropriate radioligand is available. [18F]MPPF (4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F]fluorobenzamido]ethylpiperazine) is a selective radioligand for serotonin 5-HT1A receptors. We have established that the binding potential (BP=Bmax/KD) of [18F]MPPF for cerebral 5-HT1A receptors can be assessed in human brain without arterial sampling.
The aim of this study was to assess if 5-HT1A receptor occupancy can be measured through calculation of a drug-related decrease in BP with [18F]MPPF and PET.
Six volunteers were scanned twice using a Siemens Exact HR+ camera following injection of 70+/-18 MBq [18F]MPPF (baseline and medicated conditions). Before the second scan, volunteers orally received either 3x10 mg pindolol at T=-15.5 h, T=-6.5 h, and T=-1.5 h (n=3) or 10 mg buspirone in a single dose at T=-1.5 h (n=3). Binding potentials were calculated using the simplified reference tissue model with the cerebellum as reference.
Administration of 30 mg pindolol led to a significant reduction in [18F]MPPF binding potential of 42+/-17%. In contrast, no significant reduction of [18F]MPPF binding potential was observed following administration of buspirone (5+/-17%).
These results show that [18F]MPPF can be used for measurement of drug-related 5-HT1A receptor occupancy and may be of particular interest in determining the 5-HT1A receptor interaction of new or established drugs in phase 1 and early phase 2 drug trials. Apparently, the 5-HT1A partial agonist buspirone is already clinically effective at low levels of 5-HT1A receptor occupancy.
为了更好地理解新药或已上市药物与其靶点的相互作用机制，人们对测量这种相互作用的兴趣日益增加。如果有合适的放射性配体，正电子发射断层扫描（PET）可以提供这方面的信息。[18F]MPPF（4-(2'-甲氧基苯基)-1-[2'-(N-2"-吡啶基)-p-[18F]氟苯甲酰胺基]乙基哌嗪）是一种选择性的5-羟色胺（5-HT1A）受体放射性配体。我们已经证实，无需动脉采样即可在人脑评估[18F]MPPF与脑5-HT1A受体的结合潜能（BP = Bmax/KD）。
本研究旨在评估是否可以通过计算[18F]MPPF和PET检测到的与药物相关的BP降低来测量5-HT1A受体占有率。
6名志愿者在注射70±18 MBq [18F]MPPF后（基线和用药状态），使用西门子Exact HR+相机进行两次扫描。在第二次扫描前，志愿者在T = -15.5小时、T = -6.5小时和T = -1.5小时口服3×10 mg吲哚洛尔（n = 3），或在T = -1.5小时单次口服10 mg丁螺环酮（n = 3）。使用以小脑为参考的简化参考组织模型计算结合潜能。
给予30 mg吲哚洛尔导致[18F]MPPF结合潜能显著降低42±17%。相比之下，给予丁螺环酮后未观察到[18F]MPPF结合潜能的显著降低（5±17%）。
这些结果表明，[18F]MPPF可用于测量与药物相关的5-HT1A受体占有率，在确定新药或已上市药物在1期和2期早期药物试验中的5-HT1A受体相互作用方面可能特别有意义。显然，5-HT1A部分激动剂丁螺环酮在低水平的5-HT1A受体占有率时就已经具有临床疗效。
