A Three-Part Trial to Qualify [11C]MK-6884 Positron Emission Tomography for Use as a Biomarker for Regional M4 PAM Receptor Density Quantification in the Human Brain

The purpose of this open-label, 3-part study is to investigate the safety and efficacy of [11C]MK-6884 as a positron emission tomography (PET) imaging agent for quantifying muscarinic 4 (M4) positive allosteric modulator (PAM) receptor density in brain regions of interest. The study will enroll healthy participants (Parts 1 and 2) and participants with Alzheimer's Disease (AD) (Part 3). The primary efficacy hypothesis is that the average intra-subject test-retest (T-RT) variability of tracer uptake in brain regions of interest is ≤20%.

Start Date08 Jan 2016

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with Carbon-11-MK 6884

100 Translational Medicine associated with Carbon-11-MK 6884

100 Patents (Medical) associated with Carbon-11-MK 6884

Literatures (Medical) associated with Carbon-11-MK 6884

01 Mar 2025·IEEE Transactions on Biomedical Engineering

PET Mapping of Receptor Occupancy Using Joint Direct Parametric Reconstruction

Article

Author: Normandin, Marc D. ; Najmaoui, Yassir ; Fakhri, Georges El ; Petibon, Yoann ; Chemli, Yanis ; Iredale, Philip ; Guehl, Nicolas J. ; Ouyang, Jinsong ; Belov, Vasily ; Duvvuri, Sridhar ; Marin, Thibault

Receptor occupancy (RO) studies using PET neuroimaging play a critical role in the development of drugs targeting the central nervous system (CNS). The conventional approach to estimate drug receptor occupancy consists in estimation of binding potential changes between two PET scans (baseline and post-drug injection). This estimation is typically performed separately for each scan by first reconstructing dynamic PET scan data before fitting a kinetic model to time activity curves. This approach fails to properly model the noise in PET measurements, resulting in poor RO estimates, especially in low receptor density regions.OBJECTIVEIn this work, we evaluate a novel joint direct parametric reconstruction framework to directly estimate distributions of RO and other kinetic parameters in the brain from a pair of baseline and post-drug injection dynamic PET scans.METHODSThe proposed method combines the use of regularization on RO maps with alternating optimization to enable estimation of occupancy even in low binding regions.RESULTSSimulation results demonstrate the quantitative improvement of this method over conventional approaches in terms of accuracy and precision of occupancy. The proposed method is also evaluated in preclinical in-vivo experiments using 11C-MK-6884 and a muscarinic acetylcholine receptor 4 positive allosteric modulator drug, showing improved estimation of receptor occupancy as compared to traditional estimators.CONCLUSIONThe proposed joint direct estimation framework improves RO estimation compared to conventional methods, especially in intermediate to low-binding regions.SIGNIFICANCEThis work could potentially facilitate the evaluation of new drug candidates targeting the CNS.

01 Aug 2024·Journal of Cerebral Blood Flow & Metabolism

PET imaging of M4 muscarinic acetylcholine receptors in rhesus macaques using [¹¹C]MK-6884: Quantification with kinetic modeling and receptor occupancy by CVL-231 (emraclidine), a novel positive allosteric modulator

Article

Author: Duvvuri, Sridhar ; Moon, Sung-Hyun ; Renger, John J ; MacDonagh, Alexander C ; Yokell, Daniel L ; Iredale, Philip ; Dhaynaut, Maeva ; Guehl, Nicolas J ; Belov, Vasily ; Normandin, Marc D ; Chakilam, Srinivas ; El Fakhri, Georges ; Rice, Peter A

Stimulation of the M4 muscarinic acetylcholine receptor reduces striatal hyperdopaminergia, suggesting its potential as a therapeutic target for schizophrenia. Emraclidine (CVL-231) is a novel, highly selective, positive allosteric modulator (PAM) of M4 muscarinic acetylcholine receptors i.e. acts as a modulator that increases the response of these receptors. First, we aimed to further characterize the positron emission tomography (PET) imaging and quantification performance of a recently developed M4 PAM radiotracer, [11C]MK-6884, in non-human primates (NHPs). Second, we applied these results to determine the receptor occupancy of CVL-231 as a function of dose. Using paired baseline-blocking PET scans, we quantified total volume of distribution, binding potential, and receptor occupancy. Both blood-based and reference region-based methods quantified M4 receptor levels across brain regions. The 2-tissue 4-parameter kinetic model best fitted regional [11C]MK-6884-time activity curves. Only the caudate nucleus and putamen displayed statistically significant [11C]MK-6884 uptake and dose-dependent blocking by CVL-231. For binding potential and receptor occupancy quantification, the simplified reference tissue model using the grey cerebellum as a reference region was employed. CVL-231 demonstrated dose-dependent M4 receptor occupancy in the striatum of the NHP brain and shows promise for further development in clinical trials.

01 Oct 2023·European Journal of Medicinal Chemistry

Design, synthesis and evaluation of novel 2-phenyl-3-(1H-pyrazol-4-yl)pyridine positive allosteric modulators for the M4 mAChR

Article

Author: Tobin, Andrew B ; Lu, Yao ; Christopher Choy, K H ; Shackleford, David M ; van der Westhuizen, Emma T ; Capuano, Ben ; Valant, Celine ; Thal, David M ; Jörg, Manuela ; Christopoulos, Arthur ; Scammells, Peter J ; Khajehali, Elham

Translation of muscarinic acetylcholine receptor (mAChR) agonists into clinically used therapeutic agents has been difficult due to their poor subtype selectivity. M₄ mAChR subtype-selective positive allosteric modulators (PAMs) may provide better therapeutic outcomes, hence investigating their detailed pharmacological properties is crucial to advancing them into the clinic. Herein, we report the synthesis and comprehensive pharmacological evaluation of M₄ mAChR PAMs structurally related to 1e, Me-C-c, [¹¹C]MK-6884 and [¹⁸F]12. Our results show that small structural changes to the PAMs can result in pronounced differences to baseline, potency (pEC₅₀) and maximum effect (E_max) measures in cAMP assays when compared to the endogenous ligand acetylcholine (ACh) without the addition of the PAMs. Eight selected PAMs were further assessed to determine their binding affinity and potential signalling bias profile between cAMP and β-arrestin 2 recruitment. These rigorous analyses resulted in the discovery of the novel PAMs, 6k and 6l, which exhibit improved allosteric properties compared to the lead compound, and probative in vivo exposure studies in mice confirmed that they maintain the ability to cross the blood-brain barrier, making them more suitable for future preclinical assessment.

100 Deals associated with Carbon-11-MK 6884

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 2	United States	Merck Sharp & Dohme Corp.	17 Apr 2020

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02621606 (MK-6884-001 \| 6884-001, CTgov)	Phase 1	Alzheimer Disease	20	[11C]MK-6884 (Part 1, Healthy Participants)	cwvuzghtuc(umipvxjnmc) = fplhotsain xczgidbjrr (dknujrtlmh, pyrivumait - xulpjacmum) View more	-	28 Feb 2019
				[11C]MK-6884 (Part 2, Healthy Elderly Participants)	cwvuzghtuc(umipvxjnmc) = ahsmdkismq xczgidbjrr (dknujrtlmh, xrikvmolhc - tcfolhgkkr) View more

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