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

被引：102

作者：

Hostetler, Eric D. ^{[1
]}

Joshi, Aniket D. ^{[1
]}

Sanabria-Bohorquez, Sandra ^{[1
]}

Fan, Hong ^{[1
]}

Zeng, Zhizhen ^{[1
]}

Purcell, Mona ^{[1
]}

Gantert, Liza ^{[1
]}

Riffel, Kerry ^{[1
]}

Williams, Mangay ^{[1
]}

O'Malley, Stacey ^{[1
]}

Miller, Patricia ^{[1
]}

Selnick, Harold G. ^{[1
]}

Gallicchio, Steven N. ^{[1
]}

Bell, Ian M. ^{[1
]}

Salvatore, Christopher A. ^{[1
]}

Kane, Stefanie A. ^{[1
]}

Li, Chi-Chung ^{[1
]}

Hargreaves, Richard J. ^{[1
]}

de Groot, Tjibbe ^{[2
,3
]}

Bormans, Guy ^{[4
]}

Van Hecken, Anne ^{[8
,9
]}

Derdelinckx, Inge ^{[8
,9
]}

de Hoon, Jan ^{[8
,9
]}

Reynders, Tom ^{[5
]}

Declercq, Ruben ^{[5
]}

De Lepeleire, Inge ^{[5
]}

Kennedy, W. P. ^{[6
]}

Blanchard, Rebecca ^{[6
]}

Marcantonio, Eugene E. ^{[7
]}

Sur, Cyrille ^{[1
]}

Cook, Jacquelynn J. ^{[1
]}

Van Laere, Koen ^{[2
,3
]}

Evelhoch, Jeffrey L. ^{[1
]}

机构：

[1] Merck Res Labs, West Point, PA 19486 USA

[2] Univ Hosp, Div Nucl Med, Louvain, Belgium

[3] Katholieke Univ Leuven, Louvain, Belgium

[4] Lab Radiopharm KU Leuven, Louvain, Belgium

[5] Merck Sharp & Dohme Ltd, Brussels, Belgium

[6] Merck Clin Pharmacol, Upper Gwynedd, PA USA

[7] Merck Clin Pharmacol, Kenilworth, NJ USA

[8] Univ Hosp, Ctr Clin Pharmacol, Louvain, Belgium

[9] Katholieke Univ Leuven, Louvain, Belgium

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2013年 / 347卷 / 02期

关键词：

STEM ACTIVATION; BINDING-SITES; MIGRAINE; ANTAGONISTS; POTENT; SYSTEM;

D O I：

10.1124/jpet.113.206458

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：478 / 486

页数：9

共 28 条

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