Synthesis and Characterization of [18F]JNJ-46356479 as the First 18F-Labeled PET Imaging Ligand for Metabotropic Glutamate Receptor 2

Molecular Imaging and Biology (2021)Cite this article

Abstract

Purpose

Metabotropic glutamate receptor 2 (mGluR2) has been implicated in various psychiatric and neurological disorders, such as schizophrenia and Alzheimer’s disease. We have previously developed [11C]7 as a PET radioligand for imaging mGluR2. Herein, [18F]JNJ-46356479 ([18F]8) was synthesized and characterized as the first 18F-labeled mGluR2 imaging ligand to enhance diagnostic approaches for mGluR2-related disorders.

Procedures

JNJ-46356479 (8) was radiolabeled via the copper (I)-mediated radiofluorination of organoborane 9. In vivo PET imaging experiments with [18F]8 were conducted first in C57BL/6 J mice and Sprague-Dawley rats to obtain whole body biodistribution and brain uptake profile. Subsequent PET studies were done in a cynomolgus monkey (Macaca fascicularis) to investigate the uptake of [18F]8 in the brain, its metabolic stability, as well as pharmacokinetic properties.

Results

JNJ-46356479 (8) exhibited excellent selectivity against other mGluRs. In vivo PET imaging studies showed reversible and specific binding characteristic of [18F]8 in rodents. In the non-human primate, [18F]8 displayed good in vivo metabolic stability, excellent brain permeability, fast and reversible kinetics with moderate heterogeneity across brain regions. Pre-treatment studies with compound 7 revealed time-dependent decrease of [18F]8 accumulation in mGluR2 rich regions based on SUV values with the highest decrease in the nucleus accumbens (18.7 ± 5.9%) followed by the cerebellum (18.0 ± 7.9%), the parietal cortex (16.9 ± 7.8%), and the hippocampus (16.8 ± 6.9%), similar to results obtained in the rat studies. However, the volume of distribution (VT) results derived from 2T4k model showed enhanced VT from a blocking study with compound 7. This is probably because of the potentiating effect of compound 7 as an mGluR2 PAM as well as related non-specific binding in the tissue data.

Conclusions

[18F]8 readily crosses the blood-brain barrier and demonstrates fast and reversible kinetics both in rodents and in a non-human primate. Further investigation of [18F]8 on its binding specificity would warrant translational study in human.

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Acknowledgment

mGluR1-6 and mGluR8 agonist and antagonist functional data as well as mGluR2 PAM activity were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth (email to: bryan_roth@med.unc.edu) at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll (email to: jdrisco1@mail.nih.gov) at NIMH, Bethesda MD, USA. For experimental details please refer to the PDSP web site https://pdspdb.unc.edu/pdspWeb/ (https://pdspdb.unc.edu/pdspWeb/).

Funding

This project was financially supported by NIH grants [1R01EB021708 and 1R01NS100164] and the grants [1S10RR023452-01 and 1S10OD025234-01] for the imaging instrumentation and characterization of the organic compounds as well as the NIH grants [S10OD018035 and P41EB022544] to support the blood counting and metabolite analysis equipment used in the primate studies.

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Affiliations

  1. Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, 3rd Avenue, Charlestown, MA, 02129, USA

    Gengyang Yuan, Nicolas J. Guehl, Baohui Zheng, Xiying Qu, Sung-Hyun Moon, Maeva Dhaynaut, Timothy M. Shoup, Sepideh Afshar, Georges El Fakhri, Marc D. Normandin & Anna-Liisa Brownell

  2. Department of Pharmacology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC, 27514, USA

    Hye Jin Kang

  3. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth Street, Suite 2301, Charlestown, MA, 02129, USA

    Zhaoda Zhang

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  1. Gengyang Yuan
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  2. Nicolas J. Guehl
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Corresponding authors

Correspondence to Gengyang Yuan or Anna-Liisa Brownell.

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All animal experiments were approved and done under the guidelines of the Subcommittee on Research Animals of the Massachusetts General Hospital and Harvard Medical School in accordance with the Guide of NIH for the Care and Use of Laboratory Animals.

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Yuan, G., Guehl, N.J., Zheng, B. et al. Synthesis and Characterization of [18F]JNJ-46356479 as the First 18F-Labeled PET Imaging Ligand for Metabotropic Glutamate Receptor 2. Mol Imaging Biol (2021). https://doi.org/10.1007/s11307-021-01586-0

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Key words

  • mGluR2
  • PET
  • Rodents
  • Non-human primate
  • Kinetic modeling
  • Neurological diseases