TY - JOUR T1 - In Vivo Quantification of Calcitonin Gene-Related Peptide Receptor Occupancy by Telcagepant in Rhesus Monkey and Human Brain Using the Positron Emission Tomography Tracer [<sup>11</sup>C]MK-4232 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 478 LP - 486 DO - 10.1124/jpet.113.206458 VL - 347 IS - 2 AU - Eric D. Hostetler AU - Aniket D. Joshi AU - Sandra Sanabria-Bohórquez AU - Hong Fan AU - Zhizhen Zeng AU - Mona Purcell AU - Liza Gantert AU - Kerry Riffel AU - Mangay Williams AU - Stacey O’Malley AU - Patricia Miller AU - Harold G. Selnick AU - Steven N. Gallicchio AU - Ian M. Bell AU - Christopher A. Salvatore AU - Stefanie A. Kane AU - Chi-Chung Li AU - Richard J. Hargreaves AU - Tjibbe de Groot AU - Guy Bormans AU - Anne Van Hecken AU - Inge Derdelinckx AU - Jan de Hoon AU - Tom Reynders AU - Ruben Declercq AU - Inge De Lepeleire AU - W. P. Kennedy AU - Rebecca Blanchard AU - Eugene E. Marcantonio AU - Cyrille Sur AU - Jacquelynn J. Cook AU - Koen Van Laere AU - Jeffrey L. Evelhoch Y1 - 2013/11/01 UR - http://jpet.aspetjournals.org/content/347/2/478.abstract N2 - 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 [11C]MK-4232 (2-[(8R)-8-(3,5-difluorophenyl)-6,8-[6-11C]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, [11C]MK-4232 displayed rapid brain uptake and a regional brain distribution consistent with the known distribution of CGRP-R. Monkey PET studies with [11C]MK-4232 after intravenous dosing with CGRP-R antagonists validated the ability of [11C]MK-4232 to detect changes in CGRP-R occupancy in proportion to drug plasma concentration. Application of [11C]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. ER -