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

  • ACS Pharmacol Transl Sci. 2024 Jul 10;7(8):2414-2423. doi: 10.1021/acsptsci.4c00261.
Yinlong Li  1 ,  Kenneth Dahl  2  3 ,  Peter Johnström  2  3 ,  Katarina Varnäs  3 ,  Lars Farde  3 ,  Christer Halldin  3 ,  Amy Medd  4 ,  Donna Maier  4 ,  Mark E Powell  4 ,  Jiahui Chen  1 ,  Richard Van  5 ,  Jimmy Patel  1 ,  Ahmad Chaudhary  1 ,  Yabiao Gao  1 ,  Zhendong Song  1 ,  Achi Haider  1 ,  Yihan Shao  5 ,  Charles S Elmore  4  6 ,  Steven Liang  1 ,  Magnus Schou  2  3
Affiliations
  • 1. Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States.
  • 2. PET Science Centre, Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Karolinska Institutet, Stockholm S-17176, Sweden.
  • 3. Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm S-17176, Sweden.
  • 4. Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Wilmington, Delaware 19803, United States.
  • 5. Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019-5251, United States.
  • 6. Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca Pharmaceuticals, Gothenburg 43183, Sweden.
PMID: 39144551 DOI: 10.1021/acsptsci.4c00261
Abstract

The metabotropic glutamate receptor 2 (mGluR2) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR2-targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR2 positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity (K i mGluR2 = 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, [3H]AZ12559322, revealed a heterogeneous accumulation with the highest binding in mGluR2-rich brain regions. Radioligand binding was significantly reduced by pretreatment with nonradioactive mGluR2 PAMs in brains of rats and nonhuman primates. Although positron emission tomography imaging of [11C]AZ12559322 (6a) revealed low brain uptake in a nonhuman primate, this study provides valuable guidance to further design novel isoindolone-based mGluR2 PAMs with improved brain exposure.

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