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

Hostetler, Eric D.; Joshi, Aniket; Sanabria-Bohórquez, Sandra M.; Fan, Hong; Zeng, Zhizhen; Purcell, Mona; Gantert, Liza; Riffel, Kerry; Williams, M. A.; O’Malley, Stacey; Miller, Patricia; Selnick, Harold G.; Gallicchio, Steven N.; Bell, Ian M.; Salvatore, Christopher; Kane, Stefanie A.; Li, Chi-Chung; Hargreaves, Richard; Groot, Tjibbe de; Bormans, Guy; Hecken, Anne Van; Derdelinckx, Inge; Hoon, Jan de; Reynders, Tom; Declercq, Ruben; Lepeleire, Inge De; Kennedy, William P.; Blanchard, Rebecca; Marcantonio, Eugene E.; Sur, Cyrille; Cook, Jacquelynn J.; Laere, Koen Van; Evelhoch, Jeffrey L.

doi:10.1124/jpet.113.206458

Cited by 118 publications

(109 citation statements)

References 26 publications

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“…The CSF/plasma ratio in primates for telcagepant, for example, was found to be about 1.4 % [102]. Despite these findings, low central receptor occupancy after efficacious dose (140 mg orally) of telcagepant suggests that this is not the responsible mechanism for its clinical efficacy [103]. A recent study found high-binding densities of the CGRP-RA MK-3207 in the trigeminal ganglion of rhesus monkeys, which is located outside of the BBB.…”

Section: Blood-brain Barriermentioning

confidence: 99%

Targeting CGRP: A New Era for Migraine Treatment

Goldberg

Silberstein

2015

CNS Drugs

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Migraine is a highly prevalent headache disease that typically affects patients during their most productive years. Despite significant progress in understanding the underlying pathophysiology of this disorder, its treatment so far continues to depend on drugs that, in their majority, were not specifically designed for this purpose. The neuropeptide calcitonin gene-related peptide (CGRP) has been indicated as playing a critical role in the central and peripheral pathways leading to a migraine attack. It is not surprising that drugs designed to specifically block its action are gaining remarkable attention from researchers in the field with, at least so far, a safe risk profile. In this article, we highlight the evolution from older traditional treatments to the innovative CGRP target drugs that are revolutionizing the way to approach this debilitating neurological disease. We provide a brief introduction on pathophysiology of migraine and details on the characteristic, function, and localization of CGRP to then focus on CGRP receptor antagonists (CGRP-RAs) and CGRP monoclonal antibodies (CGRP mAbs). Key PointsThe neuropeptide calcitonin gene-related peptide (CGRP) has been indicated as playing a critical role in the central and peripheral pathways leading to a migraine attack.Targeting CGRP as a specific therapeutic tool for migraine may offer similar or even better efficacy than currently available treatments without the vasoconstrictive risk factors.Further studies are necessary to determine the exact role of CGRP receptor antagonists and CGRP monoclonal antibodies in migraine with aura, allodynia, and photophobia.

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Section: Blood-brain Barriermentioning

confidence: 99%

Targeting CGRP: A New Era for Migraine Treatment

Goldberg

Silberstein

2015

CNS Drugs

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“…Moreover, functional activation of cerebellar and brainstem regions could be observed by means of PET [140] [155]. Mismatch in the recovery of brainstem and cerebellar regions resulted in the presumption that an imbalance between brain stem nuclei regulating antinociception and vascular control could be the basis of the pathogenesis of migraine [153].…”

Section: Calcitonin Gene-related Peptide and Cgrp Receptormentioning

confidence: 97%

“…The role of these CNS receptors in pain transmission (especially in migraine attacks) is yet not fully understood [153]. However, some antagonists of the CGRP receptor have been shown also in clinical trials to contribute to pain relief in migraineurs.…”

Section: Calcitonin Gene-related Peptide and Cgrp Receptormentioning

confidence: 99%

“…Hostetler et al [153] showed that the receptor occupancy in cerebellum and brain stem commonly binding CGRP ligands achieved 43% -58% if telcagepant was applied in doses tenfold larger than those used in clinical trials with efficient relief of migraine pain. Doses similar to those in a clinical phase III study resulted, however, only in a receptor occupancy between 4 and 10% suggesting that the action on central CGRP receptors was not the key component or not the only component in the action of telgacepant as an analgesic in migraine [153]. The question remained still unanswered, whether an enhancement of the occupancy of the central CGRP receptors can improve the efficacy of their antagonists.…”

Section: Cgrp Receptor Ligandsmentioning

confidence: 99%

“…The further modification of the substance resulted in the PET tracer [ 11 C]MK 4232 (14) (Figure 5) which fulfilled the requirements for neuropeptide ligands not only by its high affinity to the receptor but also because of its moderate lipophilicity (LogD 3.38), good passive cell permeability of 25 × 10 −6 cm/s and a low susceptibility for permeability-glycoprotein (P-gp) with a transport ratio of 1.7 which is lower than that of MK 8852 and MK 3207 [60]. Hostetler and colleagues [153] used MK 3207, MK 4232, telcagepant as well as the 11 C-labelled CGRPA2 which is known to be a non-brain penetrant CGRP receptor antagonist (K i 0.018 nM) in an innovative PET study. …”

Section: Cgrp Receptor Ligandsmentioning

confidence: 99%

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Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

Pissarek¹

2014

WJNS

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PET and SPECT in Drug Development

Welch¹,

Tavares²,

Pimlott³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Positron emission tomography (PET) and single‐photon emission computed tomography (SPECT) are noninvasive molecular imaging techniques that can be used to provide functional information in the living human body. They use radiolabeled compounds that bind to specific sites on a biological target, known as radiotracers, enabling us to visualize and characterize specific aspects of a biological process. This article describes these techniques and how they can be utilized in the drug development process.

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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

Cited by 118 publications

References 26 publications

Targeting CGRP: A New Era for Migraine Treatment

Targeting CGRP: A New Era for Migraine Treatment

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

PET and SPECT in Drug Development

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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

Cited by 118 publications

References 26 publications

Targeting CGRP: A New Era for Migraine Treatment

Targeting CGRP: A New Era for Migraine Treatment

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

PET and SPECT in Drug Development

Contact Info

Product

Resources

About

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