The PET tracer [11C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease

Wenping Li; Yuchuan Wang; Talakad G. Lohith; Zhizhen Zeng; Ling Tong; Robert Mazzola; Kerry Riffel; Patricia Miller; Mona Purcell; Marie Holahan; Hyking Haley; Liza Gantert; David Hesk; Sumei Ren; John Morrow; Jason Uslaner; Arie Struyk; Jenny Miu Chun Wai; Michael T. Rudd; David M. Tellers; Thomas McAvoy; Guy Bormans; Michel Koole; Koen Van Laere; Kim Serdons; Jan De Hoon; Ruben Declercq; Inge De Lepeleire; Maria B. Pascual; Paolo Zanotti-Fregonara; Meixiang Yu; Victoria Arbones; Joseph C. Masdeu; Amy Cheng; Azher Hussain; Tjerk Bueters; Matt S. Anderson; Eric D. Hostetler; Anthony S. Basile

doi:10.1126/scitranslmed.abg3684

The PET tracer [¹¹C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease

Wenping Li, Yuchuan Wang, Talakad G. Lohith, Zhizhen Zeng, Ling Tong, Robert Mazzola, Kerry Riffel, Patricia Miller, Mona Purcell, Marie Holahan, Hyking Haley, Liza Gantert, David Hesk, Sumei Ren, John Morrow, Jason Uslaner, Arie Struyk, Jenny Miu Chun Wai, Michael T. Rudd, David M. TellersThomas McAvoy, Guy Bormans, Michel Koole, Koen Van Laere, Kim Serdons, Jan De Hoon, Ruben Declercq, Inge De Lepeleire, Maria B. Pascual, Paolo Zanotti-Fregonara, Meixiang Yu, Victoria Arbones, Joseph C. Masdeu, Amy Cheng, Azher Hussain, Tjerk Bueters, Matt S. Anderson, Eric D. Hostetler, Anthony S. Basile

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [¹¹C]MK-6884 from rhesus monkeys to patients with Alzheimer's disease (AD). [³H]MK-6884/[¹¹C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo. The tracer demonstrates target engagement of positive allosteric modulators of the M4R (M4 PAMs) through competitive binding interactions. [¹¹C]MK-6884 binding is enhanced in vitro by the orthosteric M4R agonist carbachol and indirectly in vivo by the acetylcholinesterase inhibitor donepezil in rhesus monkeys and healthy volunteers, consistent with its pharmacology as a highly cooperative M4 PAM. PET imaging of [¹¹C]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BP_ND) of [11C]MK-6884. These results suggest that [¹¹C]MK-6884 is a useful target engagement biomarker for M4 PAMs but may also act as a sensitive probe of neuropathological changes in the brains of patients with AD.

Original language	English (US)
Article number	eabg3684
Pages (from-to)	eabg3684
Journal	Science translational medicine
Volume	14
Issue number	627
DOIs	https://doi.org/10.1126/scitranslmed.abg3684
State	Published - Jan 12 2022

Keywords

Acetylcholinesterase
Alzheimer Disease/diagnostic imaging
Animals
Humans
Macaca mulatta
Positron-Emission Tomography/methods
Receptors, Muscarinic

ASJC Scopus subject areas

Medicine(all)

Access to Document

10.1126/scitranslmed.abg3684

Cite this

Li, W., Wang, Y., Lohith, T. G., Zeng, Z., Tong, L., Mazzola, R., Riffel, K., Miller, P., Purcell, M., Holahan, M., Haley, H., Gantert, L., Hesk, D., Ren, S., Morrow, J., Uslaner, J., Struyk, A., Wai, J. M. C., Rudd, M. T., ... Basile, A. S. (2022). The PET tracer [¹¹C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease. Science translational medicine, 14(627), eabg3684. Article eabg3684. https://doi.org/10.1126/scitranslmed.abg3684

Li, W, Wang, Y, Lohith, TG, Zeng, Z, Tong, L, Mazzola, R, Riffel, K, Miller, P, Purcell, M, Holahan, M, Haley, H, Gantert, L, Hesk, D, Ren, S, Morrow, J, Uslaner, J, Struyk, A, Wai, JMC, Rudd, MT, Tellers, DM, McAvoy, T, Bormans, G, Koole, M, Van Laere, K, Serdons, K, De Hoon, J, Declercq, R, De Lepeleire, I, Pascual, MB, Zanotti-Fregonara, P, Yu, M, Arbones, V, Masdeu, JC, Cheng, A, Hussain, A, Bueters, T, Anderson, MS, Hostetler, ED & Basile, AS 2022, 'The PET tracer [¹¹C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease', Science translational medicine, vol. 14, no. 627, eabg3684, pp. eabg3684. https://doi.org/10.1126/scitranslmed.abg3684

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abstract = "Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [11C]MK-6884 from rhesus monkeys to patients with Alzheimer's disease (AD). [3H]MK-6884/[11C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo. The tracer demonstrates target engagement of positive allosteric modulators of the M4R (M4 PAMs) through competitive binding interactions. [11C]MK-6884 binding is enhanced in vitro by the orthosteric M4R agonist carbachol and indirectly in vivo by the acetylcholinesterase inhibitor donepezil in rhesus monkeys and healthy volunteers, consistent with its pharmacology as a highly cooperative M4 PAM. PET imaging of [11C]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BPND) of [11C]MK-6884. These results suggest that [11C]MK-6884 is a useful target engagement biomarker for M4 PAMs but may also act as a sensitive probe of neuropathological changes in the brains of patients with AD.",

keywords = "Acetylcholinesterase, Alzheimer Disease/diagnostic imaging, Animals, Humans, Macaca mulatta, Positron-Emission Tomography/methods, Receptors, Muscarinic",

author = "Wenping Li and Yuchuan Wang and Lohith, {Talakad G.} and Zhizhen Zeng and Ling Tong and Robert Mazzola and Kerry Riffel and Patricia Miller and Mona Purcell and Marie Holahan and Hyking Haley and Liza Gantert and David Hesk and Sumei Ren and John Morrow and Jason Uslaner and Arie Struyk and Wai, {Jenny Miu Chun} and Rudd, {Michael T.} and Tellers, {David M.} and Thomas McAvoy and Guy Bormans and Michel Koole and {Van Laere}, Koen and Kim Serdons and {De Hoon}, Jan and Ruben Declercq and {De Lepeleire}, Inge and Pascual, {Maria B.} and Paolo Zanotti-Fregonara and Meixiang Yu and Victoria Arbones and Masdeu, {Joseph C.} and Amy Cheng and Azher Hussain and Tjerk Bueters and Anderson, {Matt S.} and Hostetler, {Eric D.} and Basile, {Anthony S.}",

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AU - Wang, Yuchuan

AU - Lohith, Talakad G.

AU - Zeng, Zhizhen

AU - Tong, Ling

AU - Mazzola, Robert

AU - Riffel, Kerry

AU - Miller, Patricia

AU - Purcell, Mona

AU - Holahan, Marie

AU - Haley, Hyking

AU - Gantert, Liza

AU - Hesk, David

AU - Ren, Sumei

AU - Morrow, John

AU - Uslaner, Jason

AU - Struyk, Arie

AU - Wai, Jenny Miu Chun

AU - Rudd, Michael T.

AU - Tellers, David M.

AU - McAvoy, Thomas

AU - Bormans, Guy

AU - Koole, Michel

AU - Van Laere, Koen

AU - Serdons, Kim

AU - De Hoon, Jan

AU - Declercq, Ruben

AU - De Lepeleire, Inge

AU - Pascual, Maria B.

AU - Zanotti-Fregonara, Paolo

AU - Yu, Meixiang

AU - Arbones, Victoria

AU - Masdeu, Joseph C.

AU - Cheng, Amy

AU - Hussain, Azher

AU - Bueters, Tjerk

AU - Anderson, Matt S.

AU - Hostetler, Eric D.

AU - Basile, Anthony S.

PY - 2022/1/12

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N2 - Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [11C]MK-6884 from rhesus monkeys to patients with Alzheimer's disease (AD). [3H]MK-6884/[11C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo. The tracer demonstrates target engagement of positive allosteric modulators of the M4R (M4 PAMs) through competitive binding interactions. [11C]MK-6884 binding is enhanced in vitro by the orthosteric M4R agonist carbachol and indirectly in vivo by the acetylcholinesterase inhibitor donepezil in rhesus monkeys and healthy volunteers, consistent with its pharmacology as a highly cooperative M4 PAM. PET imaging of [11C]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BPND) of [11C]MK-6884. These results suggest that [11C]MK-6884 is a useful target engagement biomarker for M4 PAMs but may also act as a sensitive probe of neuropathological changes in the brains of patients with AD.

AB - Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [11C]MK-6884 from rhesus monkeys to patients with Alzheimer's disease (AD). [3H]MK-6884/[11C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo. The tracer demonstrates target engagement of positive allosteric modulators of the M4R (M4 PAMs) through competitive binding interactions. [11C]MK-6884 binding is enhanced in vitro by the orthosteric M4R agonist carbachol and indirectly in vivo by the acetylcholinesterase inhibitor donepezil in rhesus monkeys and healthy volunteers, consistent with its pharmacology as a highly cooperative M4 PAM. PET imaging of [11C]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BPND) of [11C]MK-6884. These results suggest that [11C]MK-6884 is a useful target engagement biomarker for M4 PAMs but may also act as a sensitive probe of neuropathological changes in the brains of patients with AD.

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KW - Receptors, Muscarinic

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