Dataset Information

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

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 (V_T) results derived from 2T4k model showed enhanced V_T 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.

SUBMITTER: Yuan G

PROVIDER: S-EPMC8277681 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Yuan Gengyang G Guehl Nicolas J NJ Zheng Baohui B Qu Xiying X Moon Sung-Hyun SH Dhaynaut Maeva M Shoup Timothy M TM Afshar Sepideh S Kang Hye Jin HJ Zhang Zhaoda Z El Fakhri Georges G Normandin Marc D MD Brownell Anna-Liisa AL

Molecular imaging and biology 20210208 4

<h4>Purpose</h4>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 [<sup>11</sup>C]7 as a PET radioligand for imaging mGluR2. Herein, [<sup>18</sup>F]JNJ-46356479 ([<sup>18</sup>F]8) was synthesized and characterized as the first <sup>18</sup>F-labeled mGluR2 imaging ligand to enhance diagnostic approaches for mGluR2-related disorders.<h4>Procedures</h4>JNJ-4 ...[more]

PMID: 33559035

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Dataset Information

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

Purpose

Procedures

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Purpose

Procedures

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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