Imaging the brain marijuana receptor: Development of a radioligand that binds to cannabinoid CB1 receptors in vivo
Imaging the brain marijuana receptor: Development of a radioligand that binds to cannabinoid CB1 receptors in vivo
复制标题
DOI：
10.1046/j.1471-4159.1998.70010417.x
复制
发表时间：
1998-01-01
影响因子：
4.7
通讯作者：
Makriyannis, A
中科院分区：
文献类型：
--
作者：
Gatley, SJ;Lan, R;Makriyannis, A
大麻的主要活性成分 (-)-Delta(9)-四氢大麻酚，通过与广泛分布于大脑中的大麻素 CB1 受体结合发挥其精神作用。活体人类受试者中 CB1 受体的放射性核素成像将有助于探索该受体系统目前未知的生理作用，以及大麻依赖的神经化学后果。目前可用的大麻素受体放射性配体非常亲脂，不适合体内使用。我们报告了一种新型放射性配体 [I-123]AM281{N-(morpholin-4-yl)-5-(4-([)(123)I]iodopheny)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-甲酰胺}的开发，该配体在结构上与 CB1 选择性拮抗剂 SR141716A 相关[N-(哌啶-1-基)-5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1-H-吡唑-3-甲酰胺]。狒狒单光子发射计算机断层扫描研究、小鼠脑解剖研究和大鼠脑离体放射自显影表明，静脉注射后 [I-123]AM281 快速进入大脑，结合具有适当的区域脑特异性，并且用 SR141716A 治疗后结合减少。 AM281 在体外对用 [H-3]SR141716A 标记的小脑结合位点具有低纳摩尔范围的亲和力，并且 [I-123]AM281 的结合被几种结构不同的大麻素受体配体抑制。我们得出结论，[I-123]AM281 具有适合大麻素 CB1 受体体内研究的特性，并且适合对活人大脑中的这些受体进行成像。
The major active ingredient of marijuana, (-)-Delta(9)-tetrahydrocannabinol, exerts its psychoactive effects via binding to cannabinoid CB1 receptors, which are widely distributed in the brain. Radionuclide imaging of CB1 receptors in living human subjects would help explore the presently unknown physiological roles of this receptor system, as well as the neurochemical consequences of marijuana dependence. Currently available cannabinoid receptor radioligands are exceedingly lipophilic and unsuitable for in vivo use. We report the development of a novel radioligand, [I-123]AM281{N-(morpholin-4-yl)-5-(4-([)(123)I]iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide}, that is structurally related to the CB1-selective antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide]. Baboon single photon emission computed tomography studies, mouse brain dissection studies, and ex vivo autoradiography in rat brain demonstrated rapid passage of [I-123]AM281 into the brain after intravenous injection, appropriate regional brain specificity of binding, and reduction of binding after treatment with SR141716A. AM281 has an affinity in the low nanomolar range for cerebellar binding sites labeled with [H-3]SR141716A in vitro, and binding of [I-123]AM281 is inhibited by several structurally distinct cannabinoid receptor ligands. We conclude that [I-123]AM281 has appropriate properties for in vivo studies of cannabinoid CB1 receptors and is suitable for imaging these receptors in the living human brain.