Synthesis and preliminary biological evaluation of 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile as a PET radiotracer for imaging metabotropic glutamate receptor subtype 5
- PMID: 17787003
- DOI: 10.1002/syn.20445
Synthesis and preliminary biological evaluation of 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile as a PET radiotracer for imaging metabotropic glutamate receptor subtype 5
Abstract
The metabotropic glutamate receptor subtype 5 (mGluR5) has been reported to be implicated in various neurological disorders in the central nervous system. To investigate physiological and pathological functions of mGluR5, noninvasive imaging in a living body with PET technology and an mGluR5-specific radiotracer is urgently needed. Here, we report the synthesis of 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([(18)F]FPEB) through a convenient thermal reaction as a highly specific PET radiotracer for mGluR5. The precursor and standard compounds were prepared by a coupling reaction catalyzed by palladium. Radiosynthesis of [(18)F]FPEB was performed using nitro as a leaving group replaced by [(18)F]fluoride under conventional heating condition. Biodistribution, metabolite, and microPET studies were performed using Sprague-Dawley rats. Upto 30 mCi of [(18)F]FPEB was obtained with a radiochemical yield of 5% and a specific activity of 1900 +/- 200 mCi/mumol at the end of syntheses. Biodistribution showed rapid clearance from the blood pool and fast and steady accumulation of radioactivity into the brain. Metabolite studies indicated that only 22% of [(18)F]FPEB remained in the blood system 10 min after administration, and that a metabolite existed which was much more polar than the parent tracer. MicroPET studies demonstrated that [(18)F]FPEB accumulated specifically in mGluR5-rich regions of the brain such as striatum and hippocampus, and that blockade with 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) substantially reduced the activity uptake in these regions. Selectivity was investigated by blockage with 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-caroxamide (YM-298198), a specific antagonist for mGluR1. [(18)F]FPEB was prepared conveniently and showed high specificity and selectivity toward mGluR5. It possesses the potential to be used in human studies to evaluate mGluR5 functions in various neurological disorders.
(c) 2007 Wiley-Liss, Inc.
Similar articles
-
Synthesis and characterization in monkey of [11C]SP203 as a radioligand for imaging brain metabotropic glutamate 5 receptors.Eur J Nucl Med Mol Imaging. 2012 Dec;39(12):1949-58. doi: 10.1007/s00259-012-2205-x. Epub 2012 Aug 11. Eur J Nucl Med Mol Imaging. 2012. PMID: 22885775 Free PMC article.
-
Preparation of the metabotropic glutamate receptor 5 (mGluR5) PET tracer [(18)F]FPEB for human use: An automated radiosynthesis and a novel one-pot synthesis of its radiolabeling precursor.Appl Radiat Isot. 2014 Dec;94:349-354. doi: 10.1016/j.apradiso.2014.09.006. Epub 2014 Sep 18. Appl Radiat Isot. 2014. PMID: 25305528 Free PMC article.
-
Methoxyphenylethynyl, methoxypyridylethynyl and phenylethynyl derivatives of pyridine: synthesis, radiolabeling and evaluation of new PET ligands for metabotropic glutamate subtype 5 receptors.Nucl Med Biol. 2005 Aug;32(6):631-40. doi: 10.1016/j.nucmedbio.2005.05.004. Nucl Med Biol. 2005. PMID: 16026710
-
Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP.CNS Drug Rev. 2006 Summer;12(2):149-66. doi: 10.1111/j.1527-3458.2006.00149.x. CNS Drug Rev. 2006. PMID: 16958988 Free PMC article. Review.
-
Recent developments of the PET imaging agents for metabotropic glutamate receptor subtype 5.Curr Top Med Chem. 2007;7(18):1800-5. doi: 10.2174/156802607782507394. Curr Top Med Chem. 2007. PMID: 17979788 Review.
Cited by
-
Ring-Closing Synthesis of Dibenzothiophene Sulfonium Salts and Their Use as Leaving Groups for Aromatic 18F-Fluorination.J Am Chem Soc. 2018 Sep 5;140(35):11125-11132. doi: 10.1021/jacs.8b06730. Epub 2018 Aug 22. J Am Chem Soc. 2018. PMID: 30132661 Free PMC article.
-
Preclinical evaluation and test-retest studies of [(18)F]PSS232, a novel radioligand for targeting metabotropic glutamate receptor 5 (mGlu5).Eur J Nucl Med Mol Imaging. 2015 Jan;42(1):128-37. doi: 10.1007/s00259-014-2883-7. Epub 2014 Aug 20. Eur J Nucl Med Mol Imaging. 2015. PMID: 25139517
-
Radiosynthesis and evaluation of an 18F-labeled positron emission tomography (PET) radioligand for metabotropic glutamate receptor subtype 4 (mGlu4).J Med Chem. 2014 Nov 13;57(21):9130-8. doi: 10.1021/jm501245b. Epub 2014 Oct 27. J Med Chem. 2014. PMID: 25330258 Free PMC article.
-
Direct Cu-mediated aromatic 18F-labeling of highly reactive tetrazines for pretargeted bioorthogonal PET imaging.Chem Sci. 2021 Jul 28;12(35):11668-11675. doi: 10.1039/d1sc02789a. eCollection 2021 Sep 15. Chem Sci. 2021. PMID: 34659701 Free PMC article.
-
Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome.Brain Sci. 2020 Nov 24;10(12):899. doi: 10.3390/brainsci10120899. Brain Sci. 2020. PMID: 33255214 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources