In vivo mapping of substance P receptors in brains of laboratory animals by high-resolution imaging systems
In vivo mapping of substance P receptors in brains of laboratory animals by high-resolution imaging systems
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DOI：
10.1002/syn.20363
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发表时间：
2007-04-01
期刊：
影响因子：
2.3
通讯作者：
Suhara, Tetsuya
中科院分区：
文献类型：
--
作者：
Haneda, Eisuke;Higuchi, Makoto;Suhara, Tetsuya
P 物质 (SP) 和 NK1 受体介导的神经传递与镇痛、呕吐和多种神经精神疾病（包括抑郁症和焦虑症）的病理生理学有关。迄今为止，已经进行了几项使用 NK1 受体拮抗剂的临床试验，通过配置体内分析系统，可以对表达“类人”NK1 受体的小型实验动物大脑中的 NK1 受体进行定量绘图，从而大大提高概念验证和剂量优化的临床前评估的效率。因此，我们研究了实验动物（从啮齿类动物到灵长类动物）的适用性，以及使用[F-18]氟乙基-SPA-RQ（最近建立的 NK1 受体放射性配体的修饰）进行正电子发射断层扫描 (PET) 测量的适用性。可以在清醒状态下对恒河猴进行药代动力学测定，从而避免麻醉对 SP 神经传递的影响。通过小动物专用设备获取的 PET 和磁共振图像的共同配准，可以对沙鼠和狨猴大脑中的 NK1 受体进行详细定位。本研究还揭示了 SDZ NKT 343 作为中枢 NK1 受体拮抗剂的潜力。结合额外的体外和离体放射自显影观察，我们的体内结果证明了所检查动物之间的结合模式的相似性，证明了 SPNK 通路上 PET 结果的跨物种外推。
Neurotransmission mediated by substance P (SP) and NK1 receptor has been implicated in the pathophysiology of analgesia, emesis and diverse neuropsychiatric conditions including depression and anxiety disorder. Several lines of clinical trials using NK1 receptor antagonists have been conducted to date, and the efficiency of preclinical assessments for proof of concept and dose optimization could be greatly increased by configuring an in vivo analytical system that permits quantitative mapping of NK1 receptors in the brains of small-size laboratory animals expressing "human-like" NK1 receptors. Hence, we investigated the applicability of experimental animals, ranging from rodents to primates, to positron emission tomographic (PET) measurements with [F-18]fluoroethyl-SPA-RQ a modification of a recently established radioligand for NK1 receptors. A pharmacokinetic assay could be performed for a rhesus monkey in an awake condition, which allows the circumvention of influences of anesthesia on SP neurotransmission. Coregistration of PET and magnetic resonance images acquired by small-animal-dedicated devices enabled detailed localization of NK1 receptors in the gerbil and marmoset brains. The present study also revealed the potentials of SDZ NKT 343 as an antagonist for central NK1 receptors. In conjunction with additional in vitro and ex vivo autoradiographic observations, our in vivo results have demonstrated a similarity in the binding pattern among the animals examined, justifying cross-species extrapolation of PET findings on the SPNK,pathway.