title: 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.
abstract: 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 [(11)C]MK-4232 (2-[(8R)-8-(3,5-difluorophenyl)-6,8-[6-(11)C]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, [(11)C]MK-4232 displayed rapid brain uptake and a regional brain distribution consistent with the known distribution of CGRP-R. Monkey PET studies with [(11)C]MK-4232 after intravenous dosing with CGRP-R antagonists validated the ability of [(11)C]MK-4232 to detect changes in CGRP-R occupancy in proportion to drug plasma concentration. Application of [(11)C]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.
authors: Merck Research Laboratories, West Point, Pennsylvania (E.D.H., A.D.J., S.S.-B., H.F., Z.Z., M.P., L.G., K.R., M.W., S.O., P.M. H.G.S., S.N.G., I.M.B., C.A.S., S.A.K., C.-C.L., R.J.H., C.S., J.J.C., J.L.E.); Division of Nuclear Medicine, University Hospital and KU Leuven, Leuven, Belgium (T.d.G., K.V.L.); Lab Radiopharmacy KU Leuven, Leuven, Belgium (G.B.); Merck Sharp and Dohme, Brussels, Belgium (T.R., R.D., I.D.L.); Merck Clinical Pharmacology, Upper Gwynedd, Pennsylvania (W.P.K., R.B.); Merck Clinical Pharmacology, Kenilworth, New Jersey (E.E.M.); and Center for Clinical Pharmacology, University Hospital and KU Leuven, Leuven, Belgium (A.v.H., I.D., J.d.H.).
authors: Eric D
authors: ED
authors: Hostetler
authors: Aniket D
authors: AD
authors: Joshi
authors: Sandra
authors: S
authors: Sanabria-Bohórquez
authors: Hong
authors: H
authors: Fan
authors: Zhizhen
authors: Z
authors: Zeng
authors: Mona
authors: M
authors: Purcell
authors: Liza
authors: L
authors: Gantert
authors: Kerry
authors: K
authors: Riffel
authors: Mangay
authors: M
authors: Williams
authors: Stacey
authors: S
authors: O'Malley
authors: Patricia
authors: P
authors: Miller
authors: Harold G
authors: HG
authors: Selnick
authors: Steven N
authors: SN
authors: Gallicchio
authors: Ian M
authors: IM
authors: Bell
authors: Christopher A
authors: CA
authors: Salvatore
authors: Stefanie A
authors: SA
authors: Kane
authors: Chi-Chung
authors: CC
authors: Li
authors: Richard J
authors: RJ
authors: Hargreaves
authors: Tjibbe
authors: T
authors: de Groot
authors: Guy
authors: G
authors: Bormans
authors: Anne
authors: A
authors: Van Hecken
authors: Inge
authors: I
authors: Derdelinckx
authors: Jan
authors: J
authors: de Hoon
authors: Tom
authors: T
authors: Reynders
authors: Ruben
authors: R
authors: Declercq
authors: Inge
authors: I
authors: De Lepeleire
authors: W P
authors: WP
authors: Kennedy
authors: Rebecca
authors: R
authors: Blanchard
authors: Eugene E
authors: EE
authors: Marcantonio
authors: Cyrille
authors: C
authors: Sur
authors: Jacquelynn J
authors: JJ
authors: Cook
authors: Koen
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authors: Van Laere
authors: Jeffrey L
authors: JL
authors: Evelhoch
mesh_terms: D000083:Acetanilides / Q000737:chemistry / Q000493:pharmacokinetics*; D000328:Adult; D000700:Analgesics / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000818:Animals; D001381:Azepines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002250:Carbon Radioisotopes; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008253:Macaca mulatta; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy / Q000378:metabolism; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D013045:Species Specificity; D013141:Spiro Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: C585149:2-(8-(3,5-difluorophenyl)-6,8-dimethyl-10-oxo-6,9-diazaspiro(4.5)decan-9-yl)-N-(2'-oxospiro(1,3-dihydroindene-2,3'-1H-pyrrolo(2,3-b)pyridine)-5-yl)acetamide; D000083:Acetanilides; D000700:Analgesics; D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002250:Carbon Radioisotopes; D007093:Imidazoles; D019275:Radiopharmaceuticals; D013141:Spiro Compounds; C525458:telcagepant