Radiosynthesis and Evaluation of 11C-Labeled Isoindolone-Based Positive Allosteric Modulators for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor 2.

Autor:	Li Y; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States., Dahl K; PET Science Centre, Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Karolinska Institutet, Stockholm S-17176, Sweden.; Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm S-17176, Sweden., Johnström P; PET Science Centre, Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Karolinska Institutet, Stockholm S-17176, Sweden.; Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm S-17176, Sweden., Varnäs K; Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm S-17176, Sweden., Farde L; Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm S-17176, Sweden., Halldin C; Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm S-17176, Sweden., Medd A; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Wilmington, Delaware 19803, United States., Maier D; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Wilmington, Delaware 19803, United States., Powell ME; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Wilmington, Delaware 19803, United States., Chen J; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States., Van R; Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019-5251, United States., Patel J; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States., Chaudhary A; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States., Gao Y; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States., Song Z; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States., Haider A; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States., Shao Y; Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019-5251, United States., Elmore CS; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Wilmington, Delaware 19803, United States.; Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca Pharmaceuticals, Gothenburg 43183, Sweden., Liang S; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States., Schou M; PET Science Centre, Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Karolinska Institutet, Stockholm S-17176, Sweden.; Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm S-17176, Sweden.
Jazyk:	angličtina
Zdroj:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2024 Jul 10; Vol. 7 (8), pp. 2414-2423. Date of Electronic Publication: 2024 Jul 10 (Print Publication: 2024).
DOI:	10.1021/acsptsci.4c00261
Abstrakt:	The metabotropic glutamate receptor 2 (mGluR 2 ) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR 2 -targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR 2 positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity ( K i mGluR 2 = 1.31 nM) and an excellent in vitro binding specificity of 89% while demonstrating selectivity over other mGluR subtypes (>4000-fold). Autoradiography with the radiolabeled counterpart, [ 3 H]AZ12559322, revealed a heterogeneous accumulation with the highest binding in mGluR 2 -rich brain regions. Radioligand binding was significantly reduced by pretreatment with nonradioactive mGluR 2 PAMs in brains of rats and nonhuman primates. Although positron emission tomography imaging of [ 11 C]AZ12559322 ( 6a ) revealed low brain uptake in a nonhuman primate, this study provides valuable guidance to further design novel isoindolone-based mGluR 2 PAMs with improved brain exposure. Competing Interests: The authors declare no competing financial interest. (© 2024 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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