Milak Matthew S, Severance Alin J, Ogden R Todd, Prabhakaran Jaya, Kumar J S Dileep, Majo Vattoly J, Mann J John, Parsey Ramin V
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.
J Nucl Med. 2008 Apr;49(4):587-96. doi: 10.2967/jnumed.107.046540. Epub 2008 Mar 14.
Several lines of evidence demonstrate involvement of serotonin 1A receptors (5-HT1ARs) in the pathophysiology of neuropsychiatric disorders such as depression, suicidal behavior, schizophrenia, and Alzheimer's disease. We recently published the synthesis and initial evaluation of [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (11C-MMP), a 5-HT1AR agonist. Here we determine the optimal modeling parameters for 11C-MMP under its new name, 11C-CUMI-101, in Papio anubis.
PET scans were performed on 2 adult male P. anubis; 166.5 MBq +/- 43.0 (4.50 +/- 1.16 mCi) of 11C-CUMI-101 were injected as an intravenous bolus, and emission data were collected for 120 min in 3-dimensional mode. We evaluated 4 different models (1- and 2-tissue compartment iterative and noniterative kinetic models, basis pursuit, and likelihood estimation in graphical analysis [LEGA]), using binding potential (BPF = Bmax/Kd) (Bmax = maximum number of binding sites; Kd = dissociation constant) as the outcome measure. Arterial blood sampling and metabolite-corrected arterial input function were used for full quantification of BPF. To assess the performance of each model, we compared results using 6 different metrics (percentage difference, within-subject mean sum of squares [WSMSS] for reproducibility; variance across subjects, intraclass correlation coefficient [ICC] for reliability; identifiability based on bootstrap resampling of residuals; and time stability analysis to determine minimal required scanning time) at each of 6 different scanning durations. Models were also evaluated on scans acquired after injecting the 5-HT1A antagonist [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide] [WAY100635] 0.5 mg/kg, intravenous) and the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin) [8-OH-DPAT] 2 mg/kg, intravenous).
All metabolites are more polar than 11C-CUMI-101, and no significant change in metabolites was observed in the blocking studies. The free fraction is 59% +/- 3%. We determined that 100 min of scanning time is adequate and that for the region-of-interest (ROI)-level analysis, the LEGA model gives the best results. The median test-retest percentage difference for BPF is 11.15% +/- 4.82% across all regions, WSMSS = 2.66, variance = 6.07, ICC = 0.43, and bootstrap identifiability = 0.59. Preadministration of WAY100635 and 8-OH-DPAT resulted in 87% and 76% average reductions in BPF values, respectively, across ROIs.
On the basis of the measurable free fraction, high affinity and selectivity, adequate blood-brain permeability, and favorable plasma and brain kinetics, 11C-CUMI-101 is an excellent candidate for imaging high-affinity 5-HT1ARs in humans.
多项证据表明，5-羟色胺1A受体（5-HT1ARs）参与了诸如抑郁症、自杀行为、精神分裂症和阿尔茨海默病等神经精神疾病的病理生理过程。我们最近发表了5-HT1AR激动剂[O-甲基-11C]2-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁基)-4-甲基-1,2,4-三嗪-3,5(2H,4H)二酮（11C-MMP）的合成及初步评估。在此，我们以其新名称11C-CUMI-101确定了在埃及狒狒中11C-CUMI-101的最佳建模参数。
对2只成年雄性埃及狒狒进行正电子发射断层扫描（PET）；静脉推注166.5 MBq±43.0（4.50±1.16 mCi）的11C-CUMI-101，并以三维模式采集120分钟的发射数据。我们评估了4种不同模型（单组织和双组织隔室迭代及非迭代动力学模型、基追踪以及图形分析中的似然估计[LEGA]），使用结合势（BPF = Bmax/Kd）（Bmax = 最大结合位点数；Kd = 解离常数）作为结果指标。通过动脉采血和代谢物校正的动脉输入函数对BPF进行完全定量。为评估每个模型的性能，我们在6个不同扫描时长下，使用6种不同指标（百分比差异、用于评估可重复性的受试者内均方和[WSMSS]；受试者间方差、用于评估可靠性的组内相关系数[ICC]；基于残差的自助重采样的可识别性；以及用于确定最小所需扫描时间的时间稳定性分析）比较结果。还在注射5-HT1A拮抗剂[N-(2-(4-(2-甲氧基苯基)-1-哌嗪基)乙基)-N-(2-吡啶基)环己烷甲酰胺][WAY100635] 0.5 mg/kg（静脉注射）和5-HT1A激动剂8-羟基-2-(二正丙基氨基)四氢萘)[8-OH-DPAT] 2 mg/kg（静脉注射）后采集的扫描图像上对模型进行评估。
所有代谢物的极性均高于11C-CUMI-101，在阻断研究中未观察到代谢物有显著变化。游离分数为59%±3%。我们确定100分钟的扫描时间足够，并且对于感兴趣区域（ROI）水平分析，LEGA模型给出的结果最佳。所有区域BPF的重测百分比差异中位数为11.15%±4.82%，WSMSS = 2.66，方差 = 6.07，ICC = 0.43，自助可识别性 = 0.59。预先给予WAY100635和8-OH-DPAT后，ROI中BPF值的平均降低分别为87%和76%。
基于可测量的游离分数、高亲和力和选择性、足够的血脑通透性以及良好的血浆和脑动力学，11C-CUMI-101是用于人体高亲和力5-HT1ARs成像的极佳候选物。
