Radiosynthesis and evaluation of [11C]YM-202074 as a PET ligand for imaging the metabotropic glutamate receptor type 1

Yanamoto, Kazuhiko; Konno, Fujiko; Odawara, Chika; Yamasaki, Tomoteru; Kawamura, Kazunori; Hatori, Akiko; Yui, Joji; Wakizaka, Hidekatsu; Nengaki, Nobuki; Takei, Makoto; Zhang, Ming‐Rong

doi:10.1016/j.nucmedbio.2010.03.002

Cited by 29 publications

(24 citation statements)

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“…For instance, the recently developed PET radioligand 11 C-CMGDE (16) lacks specificity for mGluR2 as it also binds to mGluR3. Drugs and imaging ligands targeting allosteric binding sites on mGluRs have been more tractable, and negative allosteric modulator PET ligands have been developed for mGluR1 (17)(18)(19) and mGluR5 (20). A radioligand that enables selective quantitative assessment of mGluR2 would be a major step forward in understanding the role of this receptor in the neurobiology of multiple brain disorders and a valuable tool for testing target engagement and dose occupancy of clinical drug leads with affinity for the same receptor site (5,21).…”

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confidence: 99%

What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of ¹¹C-JNJ-42491293, A Novel Radioligand for mGluR2

et al. 2016

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Positive allosteric modulators (PAM) of metabotropic glutamate receptor 2 (mGluR2) are a potential therapy for anxiety, schizophrenia, and addiction. Aside from pathophysiologic imaging studies, an mGluR2 PET tracer would enable confirmation of sufficient central target engagement and assist dose selection for proof-of-concept studies of PAM compounds. 11 C-JNJ-42491293, a novel high-affinity radioligand (human 50% inhibitory concentration 5 9.6 nM) for the PAM site of mGluR2, was evaluated as a selective mGluR2 PAM PET tracer. Methods: In vitro and ex vivo autoradiography binding experiments in Wistar and in mGluR2 knockout and wildtype rats as well as in vivo biodistribution and brain PET imaging studies in wildtype and mGluR2 knockout rats in a primate and in humans were performed. Results: In vitro binding studies and in vivo imaging studies in Wistar rats showed moderate brain uptake, with a distribution pattern fully consistent with the reported intracerebral distribution of mGluR2. Given these promising findings, biodistribution, dosimetry, and brain kinetic modeling of 11 C-JNJ-42491293 were determined in humans. Because of an unexpected high myocardial retention, additional 11 C-JNJ-42491293 imaging studies were performed in recently available mGluR2 knockout and wildtype rats and in a monkey using a structurally distinct mGluR2 PAM ligand with affinity for the same site, demonstrating off-target binding in vivo that could not have been anticipated from previous in vitro experiments. To date, the target of this non-mGluR2 tracer binding remains unknown. Conclusion: On the basis of in vivo selectivity issues suggested by human distribution and demonstrated in knockout rat models, 11 C-JNJ-42491293 was considered unsuitable as a specific PET ligand for in vivo imaging of mGluR2. These results emphasize the importance of elaborated in vitro/in vivo comparative studies and, when available, validation with knockout animal models or structurally distinct ligands with affinity for the same site, in radiotracer development.

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What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of ¹¹C-JNJ-42491293, A Novel Radioligand for mGluR2

et al. 2016

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“…Therefore, in vivo imaging of mGluR1 may provide crucial information about its functions in the living human brain under healthy and pathologic conditions and facilitate the development of CNS drugs targeting mGluR1. Several groups have developed radiotracers for selective imaging of mGluR1 in the human brain by PET (12)(13)(14)(15)(16)(17)(18)(19)(20). Despite these efforts, there have been no clinical studies using radioligands for mGluR1 in the human brain.…”

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Initial Human PET Studies of Metabotropic Glutamate Receptor Type 1 Ligand ¹¹C-ITMM

et al. 2013

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( 11 C-ITMM) is a potential radioligand for mapping metabotropic glutamate receptor type 1 (mGluR1) in the brain by PET. The present study was performed to determine the safety, distribution, radiation dosimetry, and initial brain imaging of 11 C-ITMM in healthy human subjects. Methods: The multiorgan biodistribution and radiation dosimetry of 11 C-ITMM were assessed in 3 healthy human subjects, who underwent 2-h whole-body PET scans. Radiation dosimetry was estimated from the normalized number of disintegrations of source organs using the OLINDA/EXM program. Five healthy human subjects underwent 90-min dynamic 11 C-ITMM scans of brain regions with arterial blood sampling. For anatomic coregistration, T1-weighted MR imaging was performed. Metabolites in plasma and urine samples were analyzed by high-performance liquid chromatography. 11 C-ITMM uptake was assessed quantitatively using a 2-tissue-compartment model. Results: There were no serious adverse events in any of the subjects throughout the study period. 11 C-ITMM PET demonstrated high uptake in the urinary bladder and gallbladder, indicating both urinary and fecal excretion of radioactivity. The absorbed dose (mGy/MBq) was highest in the urinary bladder wall (13.2 6 3.5), small intestine (9.8 6 1.7), and liver (9.1 6 2.0). The estimated effective dose for 11 C-ITMM was 4.6 6 0.3 mSv/MBq. 11 C-ITMM showed a gradual increase of radioactivity in the cerebellar cortex. The total distribution volume in the brain regions ranged from 2.61 6 0.30 (cerebellar cortex) to 0.52 6 0.17 (pons), and the rank order of the corresponding total distribution volume of 11 C-ITMM was cerebellar cortex . thalamus . frontal cortex . striatum pons, which was consistent with the known distribution of mGluR1 in the primate brain. The rate of 11 C-ITMM metabolism in plasma was moderate: at 60 min after injection, 62.2% 6 8.2% of the radioactivity in plasma was intact parent compound. Conclusion: The initial findings of the present study indicated that 11 C-ITMM PET is feasible for imaging of mGluR1 in the brain. The low effective dose will permit serial examinations in the same subjects.

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“…The brain stem is known to have negligible expression of mGluR1 by immunohistochemistry (31) and autoradiograms with several radioligands including 18 F-FITM (14,15,17,18,37). Therefore, we assumed that the pons, a part of the brain stem, could be used as a reference region.…”

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confidence: 99%

“…[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]pyrimidin-4-yl]-1,3-thiazol-2-yl]-Nmethylbenzamide ( 18 F-FITM) has been recently developed as a useful PET ligand for mGluR1 imaging in our laboratory. In this study, we aimed to measure the affinity and density of mGluR1 using PET with 18 F-FITM in rat brain under the in vivo conditions.…”

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In Vivo Measurement of the Affinity and Density of Metabotropic Glutamate Receptor Subtype 1 in Rat Brain Using ¹⁸F-FITM in Small-Animal PET

Yamasaki

Fujinaga²,

Kawamura³

et al. 2012

J Nucl Med

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Metabotropic glutamate receptor subtype 1 (mGluR1) is a crucial molecular target in the central nervous system disorders. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]pyrimidin-4-yl]-1,3-thiazol-2-yl]-Nmethylbenzamide ( 18 F-FITM) has been recently developed as a useful PET ligand for mGluR1 imaging in our laboratory. In this study, we aimed to measure the affinity and density of mGluR1 using PET with 18 F-FITM in rat brain under the in vivo conditions. Methods: Binding potentials (BP ND ) and amounts of specific binding (bound ligand concentration) at equilibrium state in brain regions were noninvasively estimated using the equilibrium analysis combined with the receptor-blocked approach (EA RBA) for kinetic analysis of 18 F-FITM PET results in place of reference tissue methods. Using BP ND and specific binding values of rats treated with multidose ligand, we performed Scatchard analyses for in vivo measurements of mGluR1 density (maximum number of binding sites, or B max ) and ligand affinity (dissociation constant, or K d ) in brain regions, respectively. Results: The pretreatment of rats with unlabeled FITM (1 mg/kg) occupied an mGluR1 binding site of 18 F-FITM by more than 99% and did not affect the input function. Hence, we used the tissue time-activity curve for receptor-blocked rats as representative of the nondisplaceable (free and nonspecific binding of radioligand) compartment. The BP ND based on EA RBA showed a high correlation with the BP ND based on invasive Logan plot graphical analysis in the thalamus, hippocampus, striatum, and cingulate cortex. The K d (nM) and B max (pmol/mL) obtained by the Scatchard analyses with the multidose ligand assays were 2.1 and 36.3, respectively, for the thalamus; 2.1 and 27.5, respectively, for the hippocampus; 1.5 and 22.2, respectively, for the striatum; and 1.5 and 20.5, respectively, for the cingulate cortex with a high confidence. Conclusion: Our study is the first to our knowledge to measure the in vivo affinity (K d and binding potential) of 18 F-FITM and mGluR1 density (B max ) with a high correlation to in vitro values in rat brain regions. This measurement using PET with 18 F-FITM would be a useful index for research about mGluR1 functions in central nervous system disorders and development of new pharmaceuticals.

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Radiosynthesis and evaluation of [11C]YM-202074 as a PET ligand for imaging the metabotropic glutamate receptor type 1

Cited by 29 publications

References 24 publications

What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of ¹¹C-JNJ-42491293, A Novel Radioligand for mGluR2

What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of ¹¹C-JNJ-42491293, A Novel Radioligand for mGluR2

Initial Human PET Studies of Metabotropic Glutamate Receptor Type 1 Ligand ¹¹C-ITMM

In Vivo Measurement of the Affinity and Density of Metabotropic Glutamate Receptor Subtype 1 in Rat Brain Using ¹⁸F-FITM in Small-Animal PET

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Radiosynthesis and evaluation of [11C]YM-202074 as a PET ligand for imaging the metabotropic glutamate receptor type 1

Cited by 29 publications

References 24 publications

What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of 11C-JNJ-42491293, A Novel Radioligand for mGluR2

What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of 11C-JNJ-42491293, A Novel Radioligand for mGluR2

Initial Human PET Studies of Metabotropic Glutamate Receptor Type 1 Ligand 11C-ITMM

In Vivo Measurement of the Affinity and Density of Metabotropic Glutamate Receptor Subtype 1 in Rat Brain Using 18F-FITM in Small-Animal PET

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What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of ¹¹C-JNJ-42491293, A Novel Radioligand for mGluR2

What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of ¹¹C-JNJ-42491293, A Novel Radioligand for mGluR2

Initial Human PET Studies of Metabotropic Glutamate Receptor Type 1 Ligand ¹¹C-ITMM

In Vivo Measurement of the Affinity and Density of Metabotropic Glutamate Receptor Subtype 1 in Rat Brain Using ¹⁸F-FITM in Small-Animal PET