Radiosynthesis of PET radiotracer as a prodrug for imaging group II metabotropic glutamate receptors in vivo

doi:10.1016/j.bmcl.2012.01.039

Bioorganic & Medicinal Chemistry Letters

Volume 22, Issue 5, 1 March 2012, Pages 1958-1962

https://doi.org/10.1016/j.bmcl.2012.01.039 Get rights and content

Abstract

Group II metabotropic glutamate receptors (mGluRs) have been implicated in a variety of neurological and psychiatric disorders in recent studies. As a noninvasive medical imaging technique and a powerful tool in neurological research, positron emission tomography (PET) offers the possibility to visualize and study group II mGluRs in vivo under physiologic and pathologic conditions. We synthesized a PET tracer, (S,S,S)-2-(2-carboxycyclopropyl)-2-(3-[¹¹C]methoxyphenethyl) glycine dimethyl ester ([¹¹C]CMGDE), as a prodrug for group II mGluRs, and studied its preliminary biological properties in Sprague-Dawley rats to visualize group II mGluRs. The microPET studies demonstrated that [¹¹C]CMGDE readily penetrated into the brain and the radiotracer generated from [¹¹C]CMGDE had fast reversible binding in the group II mGluRs rich regions including striatum, hippocampus and different cortical areas. Blocking studies with LY341495 showed 20–30% decrease of binding of the radiotracer generated from [¹¹C]CMGDE in all brain areas with the highest decrease in the striatum 31.5 ± 3.2%. The results show [¹¹C]CMGDE is the first PET tracer that is brain penetrating and can be used to image group II mGluRs in vivo.

Graphical abstract

Section snippets

Acknowledgment

This work was supported by the NIH-NIBIB R01EB-012864 and NIH-NIMH R01MH-091684 to A-LB.

References and notes (28)

R.T. Ngomba et al.
Neuropharmacology
(2005)
R.X. Moldrich et al.
Eur. J. Pharmacol.
(2003)
P.J. Kenny et al.
Trends Pharmacol. Sci.
(2004)
G.J. Marek
Curr. Opin. Pharmacol.
(2004)
A.E. Kingston et al.
Neuropharmacology
(1998)
S. Chaki et al.
Neuropharmacology
(2004)
A. Pilc et al.
Biochem. Pharmacol.
(2008)
J.Q. Wang et al.
Curr. Med. Imaging Rev.
(2007)
D.D. Schoepp et al.
Stress
(2003)
D.D. Schoepp et al.
Curr. Drug Targets: CNS Neurol. Disord.
(2002)

L.E. Chavez-Noriega et al.

Curr. Drug Targets: CNS Neurol. Disord.

(2002)

M.A. Varney et al.

Curr. Drug Targets: CNS Neurol. Disord.

(2002)

S. Wolfarth et al.

Amino Acids

(2000)

M.T. Rudd et al.

Curr. Top. Med. Chem.

(2005)

Cited by (21)

3-(Cyclopropylmethyl)-7-((4-(4-[11C]methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine: Synthesis and preliminary evaluation for PET imaging of metabotropic glutamate receptor subtype 2
2020, Bioorganic and Medicinal Chemistry Letters
Selective metabotropic glutamate receptor 2 (mGluR2) inhibitors have been demonstrated to show therapeutic effects by improving alleviating symptoms of schizophrenic patients in clinical studies. Herein we report the synthesis and preliminary evaluation of a ¹¹C-labeled positron emission tomography (PET) tracer originating from a mGluR2 inhibitor, 3-(cyclopropylmethyl)-7-((4-(4-methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (CMTP, 1a). [¹¹C]CMTP ([¹¹C]1a) was synthesized by O-[¹¹C]methylation of desmethyl precursor 1b with [¹¹C]methyl iodide in 19.7 ± 8.9% (n = 10) radiochemical yield (based on [¹¹C]CO₂) with >98% radiochemical purity and >74 GBq/μmol molar activity. Autoradiography study showed that [¹¹C]1a possessed moderate in vitro specific binding to mGluR2 in the rat brain, with a heterogeneous distribution of radioactive accumulation in the mGluR2-rich brain tissue sections, such as the cerebral cortex and striatum. PET study indicated that [¹¹C]1a was able to cross the blood–brain barrier and enter the brain, but had very low specific binding in the rat brain. Further optimization for the chemical structure of 1a is necessary to increase binding affinity to mGluR2 and then improve in vivo specific binding in brain.
Synthesis and in vitro evaluation of three novel radiotracers for imaging of metabotropic glutamate receptor subtype 2 in rat brain
2017, Bioorganic and Medicinal Chemistry Letters
The purpose of this study was to develop three new radiotracers, 1-(cyclopropylmethyl)-4-([¹¹C/¹⁸F]substituted-phenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([¹¹C]1, [¹¹C]2, and [¹⁸F]4), and to examine their specific bindings with metabotropic glutamate receptor subtype 2 (mGluR2) in rat brain sections by using in vitro autoradiography. These compounds were found to possess potent in vitro binding affinities (K_i: 8.0–34.1 nM) for mGluR2 in rat brain homogenate. [¹¹C]1, [¹¹C]2, and [¹⁸F]4 were synthesized by [¹¹C/¹⁸F]alkylation of the corresponding phenol precursors with [¹¹C]methyl iodide or [¹⁸F]fluoroethyl bromide with >98% radiochemical purity and 80–130 GBq/μmol specific activity at the end of synthesis. In vitro autoradiography indicated that these radiotracers showed heterogeneous specific bindings in mGluR2-rich brain regions, such as the cerebral cortex, striatum, hippocampus, and granular layer of the cerebellum.
Synthesis and evaluation of 1-(cyclopropylmethyl)-4-(4-[11C]methoxyphenyl)-piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([11C]CMDC) for PET imaging of metabotropic glutamate receptor 2 in the rat brain
2017, Bioorganic and Medicinal Chemistry
Citation Excerpt :
Positron emission tomography (PET) radiotracers have been widely used to visualize brain receptors and their functional relationships with brain disorders. To date, several PET radiotracers for mGluR2 have been reported.16–20 The first PET radiotracer [11C]CMGDE developed for mGluR2 could not be used for imaging studies because blocking studies showed only 20–30% reduced brain uptake.16
Brain metabotropic glutamate receptor 2 (mGluR2) has been proposed as a therapeutic target for the treatment of schizophrenia-like symptoms arising from increased glutamate transmission in the forebrain. However, there does not exist a reliable tool for the study of mGluR2 in human neuroimaging. The purpose of this study was to radiosynthesize 1-(cyclopropylmethyl)-4-(4-[¹¹C]methoxyphenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([¹¹C]CMDC) and evaluate its potential as a positron emission tomography (PET) radiotracer for imaging mGluR2 in the rat brain. CMDC, a positive allosteric modulator of mGluR2, showed potent functional activity (EC₅₀: 98 nM) for human mGluR2 in vitro. [¹¹C]CMDC was synthesized by O-[¹¹C]methylation of 1-(cyclopropylmethyl)-4-(4-hydroxyphenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1) with [¹¹C]methyl iodide. [¹¹C]CMDC (2.2 ± 0.9 GBq; n = 20) was obtained from [¹¹C]CO₂ of 14.0–17.8 GBq with >98% radiochemical purity and 86–150 GBq/μmol specific activity at the end of synthesis. In vitro autoradiography indicated that [¹¹C]CMDC binding was expressed (>50% of total binding) in mGluR2-rich brain regions including the cerebral cortex, striatum and hippocampus. However, small-animal PET showed low in vivo specific binding of [¹¹C]CMDC in the rat brain. While [¹¹C]CMDC has limited potential as a PET tracer for brain mGluR2, it can be used to develop new radiotracers with improved behaviors.
Co-operative binding assay for the characterization of mGlu<inf>4</inf> allosteric modulators
2015, Neuropharmacology
Citation Excerpt :
The glutamate binding site targeted drugs (such as compound 2 in Fig. 1) suffer from receptor specificity and the search for molecules that behave as allosteric modulators has led to finding of small molecular scaffolds targeting to other distinct binding cavities of the mGlu4 (Christopoulos, 2002). The targeting of distinct allosteric binding site of mGlus with small molecular scaffolds made it possible to non-invasively image these receptors using nuclear medicine technologies, which have increased the knowledge of mGlus and mGlu targeting drugs in multiple diseases (Black et al., 2010; Drouin-Ouellet et al., 2011; Kil et al., 2013, 2014a, 2014b; Wang et al., 2012). During the last decades there has been a substantial progress in identifying positive allosteric modulators (PAM) for mGlu4 (Conn et al., 2009).
The interest in the role of metabotropic glutamate receptor 4 (mGlu₄) in CNS related disorders has increased the need for methods to investigate the binding of allosteric drug candidates. Our aim is to present the first fully characterized in vitro binding assay of mGlu₄ positive allosteric modulators (PAMs). Results suggest that mGlu₄ PAMs have characteristic co-operative binding with orthosteric glutamate, which offers a notable insight to the further development of mGlu₄ targeted therapies.
Visualizing GABA transporters in vivo: an overview of reported radioligands and future directions
2023, EJNMMI Research
Synthesis and Characterization of 5-(2-Fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2 H-pyrano[2,3- b]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2
2022, Journal of Medicinal Chemistry

View all citing articles on Scopus

View full text

Article preview

Bioorganic & Medicinal Chemistry Letters

Abstract

Graphical abstract

Section snippets

Acknowledgment

References and notes (28)

Neuropharmacology

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Curr. Opin. Pharmacol.

Neuropharmacology

Neuropharmacology

Biochem. Pharmacol.

Curr. Med. Imaging Rev.

Stress

Curr. Drug Targets: CNS Neurol. Disord.

Curr. Drug Targets: CNS Neurol. Disord.

Curr. Drug Targets: CNS Neurol. Disord.

Amino Acids

Curr. Top. Med. Chem.

Cited by (21)

3-(Cyclopropylmethyl)-7-((4-(4-[<sup>11</sup>C]methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine: Synthesis and preliminary evaluation for PET imaging of metabotropic glutamate receptor subtype 2

Synthesis and in vitro evaluation of three novel radiotracers for imaging of metabotropic glutamate receptor subtype 2 in rat brain

Synthesis and evaluation of 1-(cyclopropylmethyl)-4-(4-[<sup>11</sup>C]methoxyphenyl)-piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([<sup>11</sup>C]CMDC) for PET imaging of metabotropic glutamate receptor 2 in the rat brain

Co-operative binding assay for the characterization of mGlu<inf>4</inf> allosteric modulators

Visualizing GABA transporters in vivo: an overview of reported radioligands and future directions

Synthesis and Characterization of 5-(2-Fluoro-4-[<sup>11</sup>C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2 H-pyrano[2,3- b]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2