Distinctive In Vivo Kinetics of the New σ1 Receptor Ligands (R)-(+)- and (S)-(-)-18F-Fluspidine in Porcine Brain
Distinctive In Vivo Kinetics of the New σ1 Receptor Ligands (R)-(+)- and (S)-(-)-18F-Fluspidine in Porcine Brain
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DOI：
10.2967/jnumed.114.137562
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发表时间：
2014-10-01
影响因子：
9.3
通讯作者：
Sabri, Osama
中科院分区：
文献类型：
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作者：
Brust, Peter;Deuther-Conrad, Winnie;Sabri, Osama
由于它们参与生长和存活信号级联，sigma（1）受体（sigma（1）Rs）代表了治疗癌症和几种脑部疾病（如抑郁症和神经变性）的新靶点。从一系列sigma R-1-特异性F-18-氟烷基化螺环哌啶中，我们选择F-18-氟斯匹定用于详细研究（R）-（+）-和（S）-（-）-对映异构体的体内动力学，以确定其在人体中成像的潜力。研究方法：使用手性制备型高效液相色谱法获得用于放射性标记的对映体纯甲苯磺酸盐前体，并在合成模块中通过与K-F-18-F-Kryptofix 222-碳酸酯络合物的亲核取代用于两种F-18-氟匹定对映体的放射性合成。在基线和阻断条件下，使用高选择性sigma R-1激动剂SA 4503，通过动态PET研究在仔猪中研究脑药代动力学。计算24个MR定义的脑区的标准化摄取值（SUV）。测定了（S）-（-）-和（R）-（+）-F-18-氟匹定的总分布容积（V-T）和结合势（k3 '/k4）。此外，通过使用Logan图的图形分析估计VT值。结果：得到了对映体纯度较高的（S）-和（R）-甲苯磺酸酯（对映体过量分别>98%和>96%）。在约70分钟内合成（S）-（-）-和（R）-（+）-F-18-氟斯匹定（放射化学产率，35%-45%;比活度，650-870 GBq/μ mol;放射化学纯度，>99%）。两种放射性示踪剂显示不同的脑摄取动力学。虽然最初的脑摄取相似，但研究结束时的SUV显著不同（P < 0.05），（R）-（+）F-18-氟螺啶显示出约60%-150%的高值。施用SA 4503使两种放射性示踪剂的SUV几乎相等地降低约65%。此外，在阻断条件下，几乎所有区域的k3'均显著降低（（S）-（-）-F-18-fluspidine，-90%-95%;（R）-（+）F-18-fluspidine，-70%-90%），而对k（4）的影响因特定脑区而异。VT估计的图形分析使用Logan图和完全非线性动力学分析显示显着抑制两种放射性示踪剂在阻断条件下。结论：（S）-（-）-和（R）-（+）-F-18-fluspidine似乎都适用于人体中的sigma R-1成像。（S）-（-）-F-18-fluspidine和（R）-（+）-F-18-fluspidine的不同药代动力学可能具有应用于不同病理状况的诊断的潜力。
Because of their involvement in growth and survival signaling cascades, the sigma(1) receptors (sigma(1)Rs) represent a novel target for the treatment of cancer and several brain diseases such as depression and neurodegeneration. From a series of sigma R-1-specific F-18-fluoroalkylated spirocyclic piperidines, we have chosen F-18-fluspidine for detailed investigation of the in vivo kinetics of the (R)-(+)- and (S)-(-)-enantiomers to identify their potential for imaging in humans. Methods: Enantiopure tosylate precursors for radiolabeling were obtained using chiral preparative high-performance liquid chromatography and used for radiosynthesis of both F-18-fluspidine enantiomers by nucleophilic substitution with K-F-18-F-Kryptofix 222-carbonate complex in a synthesis module. Brain pharmacokinetics were investigated by dynamic PET studies in piglets under baseline and blocking conditions using the highly selective sigma R-1 agonist SA4503. Standardized uptake values (SUVs) were calculated for 24 MR-defined brain regions. Total distribution volume (V-T) and binding potentials (k3'/k4) of (S)-(-)- and (R)-(+)-F-18-fluspidine were estimated. Furthermore, VT values were estimated by graphical analysis using Logan plots. Results: The (S)- and (R)-tosylates were obtained in excellent enantiomeric purities (>98% and >96% enantiomeric excess, respectively). (S)-(-)- and (R)-(+)-F-18-fluspidine were synthesized within approximately 70 min (radiochemical yield, 35%-45%; specific activity, 650-870 GBq/mu mol; radiochemical purity, >99%). Both radiotracers displayed different brain uptake kinetics. Although the initial brain uptake was similar, the SUV at the end of the study differed significantly (P < 0.05), with (R)-(+)F-18-fluspidine showing about 60%-150% higher values. Administration of SA4503 reduced SUV almost equally for both radiotracers by approximately 65%. Furthermore, k3' was significantly decreased under blocking conditions in almost all regions ((S)-(-)-F-18-fluspidine, -90%-95%; (R)-(+)F-18-fluspidine, -70%-90%) whereas effects on k(4) differed according to the particular brain region. VT estimated by both graphical analysis using Logan plots and full nonlinear kinetic analysis revealed significant inhibition for both radiotracers under blocking conditions. Conclusion: Both (S)-(-)- and (R)-(+)-F-18-fluspidine appear to be suitable for sigma R-1 imaging in humans. The different pharmacokinetics of (S)-(-)-F-18-fluspidine and (R)-(+)-F-18-fluspidine may have the potential for application in the diagnostics of different pathologic conditions.