In Vitro Pharmacological Characterization and In Vivo Validation of LSN3172176 a Novel M1 Selective Muscarinic Receptor Agonist Tracer Molecule for Positron Emission Tomography.

Autor: Mogg AJ; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.) mogg_adrian@lilly.com., Eessalu T; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Johnson M; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Wright R; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Sanger HE; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Xiao H; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Crabtree MG; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Smith A; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Colvin EM; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Schober D; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Gehlert D; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Jesudason C; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Goldsmith PJ; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Johnson MP; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Felder CC; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Barth VN; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.)., Broad LM; Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom (A.J.M., H.E.S., M.G.C., A.S., E.M.C., P.J.G., L.M.B.) and Eli Lilly & Co. Ltd., Lilly Corporate Center, Indianapolis, Indiana (T.E., M.J., R.W., H.X., D.S., D.G., C.J., M.P.J., C.C.F., V.N.B.).
Jazyk: angličtina
Zdroj: The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2018 Jun; Vol. 365 (3), pp. 602-613. Date of Electronic Publication: 2018 Apr 11.
DOI: 10.1124/jpet.117.246454
Abstrakt: In the search for improved symptomatic treatment options for neurodegenerative and neuropsychiatric diseases, muscarinic acetylcholine M1 receptors (M1 mAChRs) have received significant attention. Drug development efforts have identified a number of novel ligands, some of which have advanced to the clinic. However, a significant issue for progressing these therapeutics is the lack of robust, translatable, and validated biomarkers. One valuable approach to assessing target engagement is to use positron emission tomography (PET) tracers. In this study we describe the pharmacological characterization of a selective M1 agonist amenable for in vivo tracer studies. We used a novel direct binding assay to identify nonradiolabeled ligands, including LSN3172176, with the favorable characteristics required for a PET tracer. In vitro functional and radioligand binding experiments revealed that LSN3172176 was a potent partial agonist (EC 50 2.4-7.0 nM, E max 43%-73%), displaying binding selectivity for M1 mAChRs (K d = 1.5 nM) that was conserved across species (native tissue K d = 1.02, 2.66, 8, and 1.03 at mouse, rat, monkey, and human, respectively). Overall selectivity of LSN3172176 appeared to be a product of potency and stabilization of the high-affinity state of the M1 receptor, relative to other mAChR subtypes (M1 > M2, M4, M5 > M3). In vivo, use of wild-type and mAChR knockout mice further supported the M1-preferring selectivity profile of LSN3172176 for the M1 receptor (78% reduction in cortical occupancy in M1 KO mice). These findings support the development of LSN3172176 as a potential PET tracer for assessment of M1 mAChR target engagement in the clinic and to further elucidate the function of M1 mAChRs in health and disease.
(Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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