Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland 20892-2035, USA.
J Nucl Med. 2010 Jan;51(1):112-20. doi: 10.2967/jnumed.109.067074. Epub 2009 Dec 15.
We recently demonstrated that (11)C-MePPEP, a PET ligand for CB(1) receptors, has such high uptake in the human brain that it can be imaged for 210 min and that receptor density can be quantified as distribution volume (V(T)) using the gold standard of compartmental modeling. However, (11)C-MePPEP had relatively poor retest and intersubject variabilities, which were likely caused by errors in the measurements of radioligand in plasma at low concentrations by 120 min. We sought to find an analog of (11)C-MePPEP that would provide more accurate plasma measurements. We evaluated several promising analogs in the monkey brain and chose the (18)F-di-deutero fluoromethoxy analog ((18)F-FMPEP-d(2)) to evaluate further in the human brain.
(11)C-FMePPEP, (18)F-FEPEP, (18)F-FMPEP, and (18)F-FMPEP-d(2) were studied in 5 monkeys with 10 PET scans. We calculated V(T) using compartmental modeling with serial measurements of unchanged parent radioligand in arterial plasma and radioactivity in the brain. Nonspecific binding was determined by administering a receptor-saturating dose of rimonabant, an inverse agonist at the CB(1) receptor. Nine healthy human subjects participated in 17 PET scans using (18)F-FMPEP-d(2), with 8 subjects having 2 PET scans to assess retest variability. To identify sources of error, we compared intersubject and retest variability of brain uptake, arterial plasma measurements, and V(T).
(18)F-FMPEP-d(2) had high uptake in the monkey brain, with greater than 80% specific binding, and yielded less radioactivity uptake in bone than did (18)F-FMPEP. High brain uptake with (18)F-FMPEP-d(2) was also observed in humans, in whom V(T) was well identified within approximately 60 min. Retest variability of plasma measurements was good (16%); consequently, V(T) had a good retest variability (14%), intersubject variability (26%), and intraclass correlation coefficient (0.89). V(T) increased after 120 min, suggesting an accumulation of radiometabolites in the brain. Radioactivity accumulated in the skull throughout the entire scan but was thought to be an insignificant source of data contamination.
Studies in monkeys facilitated our development and selection of (18)F-FMPEP-d(2), compared with (18)F-FMPEP, as a radioligand demonstrating high brain uptake, high percentage of specific binding, and reduced uptake in bone. Retest analysis in human subjects showed that (18)F-FMPEP-d(2) has greater precision and accuracy than (11)C-MePPEP, allowing smaller sample sizes to detect a significant difference between groups.
我们最近证明，（11）C-MePPEP，一种用于 CB（1）受体的 PET 配体，在人脑中有很高的摄取率，可以在 210 分钟内成像，并且可以使用房室模型的金标准定量受体密度作为分布容积（V（T））。然而，（11）C-MePPEP 的复测和组间变异性相对较差，这可能是由于在 120 分钟时通过等离子体中放射性配体的低浓度进行测量时存在误差。我们试图寻找一种类似（11）C-MePPEP 的化合物，它可以提供更准确的血浆测量。我们在猴脑中评估了几种有前途的类似物，并选择了（18）F-二去氘氟甲氧基类似物（（18）F-FMPEP-d（2））进一步在人脑进行评估。
在 5 只猴子中进行了 10 次 PET 扫描，研究了（11）C-FMePPEP、（18）F-FEPEP、（18）F-FMPEP 和（18）F-FMPEP-d（2）。我们使用带有动脉血浆中未改变的母体放射性配体的连续测量的房室模型来计算 V（T），并使用放射性配体在大脑中的放射性来计算 V（T）。通过给予 CB（1）受体的反向激动剂利莫那班来确定非特异性结合。9 名健康的人类受试者参与了 17 次使用（18）F-FMPEP-d（2）的 PET 扫描，其中 8 名受试者进行了 2 次 PET 扫描以评估复测变异性。为了确定误差的来源，我们比较了脑摄取、动脉血浆测量和 V（T）的组间和复测变异性。
（18）F-FMPEP-d（2）在猴脑中具有高摄取率，特异性结合率超过 80%，并且与（18）F-FMPEP 相比，在骨骼中的放射性摄取率较低。（18）F-FMPEP-d（2）在人类中也观察到高脑摄取，在大约 60 分钟内即可很好地识别 V（T）。血浆测量的复测变异性良好（16%）；因此，V（T）具有良好的复测变异性（14%）、组间变异性（26%）和组内相关系数（0.89）。120 分钟后 V（T）增加，表明放射性代谢物在大脑中积累。整个扫描过程中，放射性物质在颅骨中积累，但被认为是数据污染的一个不重要来源。
与（18）F-FMPEP 相比，在猴脑中的研究促进了我们对（18）F-FMPEP-d（2）的开发和选择，（18）F-FMPEP-d（2）作为一种放射性配体，具有高脑摄取率、高特异性结合率和降低骨骼摄取率的特点。在人类受试者中的复测分析表明，（18）F-FMPEP-d（2）比（11）C-MePPEP 具有更高的精度和准确性，允许使用更小的样本量来检测组间的显著差异。
