Discovery of [11C]MK-6884: a positron emission tomography (PET) imaging agent for the study of M4 muscarinic receptor positive allosteric modulators (PAMs) in neurodegenerative diseases

Tong, L. et al. (2020) Discovery of [11C]MK-6884: a positron emission tomography (PET) imaging agent for the study of M4 muscarinic receptor positive allosteric modulators (PAMs) in neurodegenerative diseases. Journal of Medicinal Chemistry, 63(5), pp. 2411-2425. (doi: 10.1021/acs.jmedchem.9b01406) (PMID:32101422)

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Abstract

The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Thomson, Dr Fiona
Authors: Tong, L., Li, W., Lo, M. M.-C., Gao, X., Wai, J. M.-C., Rudd, M. T., Tellers, D. M., Joshi, A., Zeng, Z., Miller, P., Salinas, C., Riffel, K., Haley, H. D., Purcell, M., Holahan, M., Gantert, L., Schubert, J. W., Jones, K., Mulhearn, J., Egbertson, M., Meng, Z., Hanney, B., Gomez, R., Harrison, S. T., McQuade, P., Bueters, T., Uslaner, J. M., Morrow, J., Thomson, F., Kong, J.-R., Liao, J., Selyutin, O., Bao, J., Hastings, N. B., Agrawal, S., Magliaro, B. C., Monsma, F. J., Smith, M. D., Risso, S., Hesk, D., Hostetler, E. D., and Mazzola, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Medicinal Chemistry
Publisher:American Chemical Society
ISSN:0022-2623
ISSN (Online):1520-4804
Published Online:26 February 2020
Copyright Holders:Copyright © 2020 American Chemical Society
First Published:First published in Journal of Medicinal Chemistry 63(5):2411-2425
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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