In Vivo Quantification of Calcitonin Gene-Related Peptide Receptor Occupancy by Telcagepant in Rhesus Monkey and Human Brain Using the Positron Emission Tomography Tracer [11C]MK-4232
In Vivo Quantification of Calcitonin Gene-Related Peptide Receptor Occupancy by Telcagepant in Rhesus Monkey and Human Brain Using the Positron Emission Tomography Tracer [11C]MK-4232
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DOI：
10.1124/jpet.113.206458
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发表时间：
2013-11-01
影响因子：
3.5
通讯作者：
Evelhoch, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Hostetler, Eric D.;Joshi, Aniket D.;Evelhoch, Jeffrey L.
降钙素基因相关肽 (CGRP) 是一种有效的神经肽，其激动剂与外周 CGRP 受体 (CGRP-R) 的相互作用可促进血管舒张、神经源性炎症和三叉血管感觉激活。这一过程与偏头痛的病因有关，临床开发中的 CGRP-R 拮抗剂已被证明可有效治疗人类偏头痛相关疼痛。 CGRP-R 在外周以及中枢神经系统的血管平滑肌和感觉三叉神经元和纤维上表达。然而，尚不清楚中枢 CGRP-R 的抑制在缓解偏头痛中起什么作用。为此，CGRP-R 正电子发射断层扫描 (PET) 示踪剂 [C-11]MK-4232 (2-[(8R)-8-(3,5-二氟苯基)-6,8-[6-C-11]二甲基-10-氧代-6,9-二氮杂螺[4.5]癸-9-y l]-N-[(2R)-2'-氧代螺[1,3-二氢茚-2,3'-1H-吡咯并[2,3-b]吡啶]-5-基]乙酰胺) 被发现并开发用于临床 PET 研究。在恒河猴和人类中，[C-11]MK-4232 显示出快速的大脑摄取和与已知的 CGRP-R 分布一致的区域大脑分布。静脉注射 CGRP-R 拮抗剂后使用 [C-11]MK-4232 进行的猴 PET 研究验证了 [C-11]MK-4232 检测 CGRP-R 占据与药物血浆浓度成比例变化的能力。 [C-11]MK-4232 在人类 PET 研究中的应用表明，替卡格泮在有效剂量（140 mg PO）下仅实现了较低的受体占有率。因此，偏头痛疗效不太可能需要拮抗中枢 CGRP-R。然而，尚不清楚中枢 CGRP-R 的高拮抗作用是否可以提供额外的治疗益处。
Calcitonin gene-related peptide (CGRP) is a potent neuropeptide whose agonist interaction with the CGRP receptor (CGRP-R) in the periphery promotes vasodilation, neurogenic inflammation and trigeminovascular sensory activation. This process is implicated in the cause of migraine headaches, and CGRP-R antagonists in clinical development have proven effective in treating migraine-related pain in humans. CGRP-R is expressed on blood vessel smooth muscle and sensory trigeminal neurons and fibers in the periphery as well as in the central nervous system. However, it is not clear what role the inhibition of central CGRP-R plays in migraine pain relief. To this end, the CGRP-R positron emission tomography (PET) tracer [C-11]MK-4232 (2-[(8R)-8-(3,5-difluorophenyl)-6,8-[6-C-11]dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(2R)-2'-oxospiro[1,3-dihydroindene-2,3'-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide) was discovered and developed for use in clinical PET studies. In rhesus monkeys and humans, [C-11]MK-4232 displayed rapid brain uptake and a regional brain distribution consistent with the known distribution of CGRP-R. Monkey PET studies with [C-11]MK-4232 after intravenous dosing with CGRP-R antagonists validated the ability of [C-11]MK-4232 to detect changes in CGRP-R occupancy in proportion to drug plasma concentration. Application of [C-11]MK-4232 in human PET studies revealed that telcagepant achieved only low receptor occupancy at an efficacious dose (140 mg PO). Therefore, it is unlikely that antagonism of central CGRP-R is required for migraine efficacy. However, it is not known whether high central CGRP-R antagonism may provide additional therapeutic benefit.