INTRODUCTION: Developing positron emission tomography (PET) ligands for imaging metabotropic glutamate receptor type 1 (mGluR1) is important for studying its role in the central nervous system. N-cyclohexyl-6-{[N-(2-methoxyethyl)-N-methylamino]methyl}-N-methylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-202074) exhibited high binding affinity for mGluR1 (K(i)=4.8 nM), and selectivity over other mGluRs in vitro. The purpose of this study was to label YM-202074 with carbon-11 and to evaluate in vitro and in vivo characteristics of [(11)C]YM-202074 as a PET ligand for mGluR1 in rodents. METHODS: [(11)C]YM-202074 was synthesized by N-[(11)C]methylation of its desmethyl precursor with [(11)C]methyl iodide. The in vitro and in vivo brain regional distributions were determined in rats using autoradiography and PET, respectively. RESULTS: [(11)C]YM-202074 (262-630 MBq, n=5) was obtained with radiochemical purity of >98% and specific activity of 27-52 GBq/mumol at the end of synthesis, starting from [(11)C]CO(2) of 19.3-21.5 GBq. In vitro autoradiographic results showed that the high specific binding of [(11)C]YM-202074 for mGluR1 was presented in the cerebellum, thalamus and hippocampus, which are known as mGluR1-rich regions. In ex vivo autoradiography and PET studies, the radioligand was specifically distributed in the cerebellum, although the uptake was low. Furthermore, the regional distribution was fairly uniform in the whole brain by pretreatment with JNJ16259685 (a mGluR1 antagonist). However, radiometabolite(s) was detected in the brain. CONCLUSIONS: From these results, especially considering the low brain uptake and the influx of radiometabolite(s) into brain, [(11)C]YM-202074 may not be a useful PET ligand for in vivo imaging of mGluR1 in the brain. Copyright 2010 Elsevier Inc. All rights reserved.
INTRODUCTION: Developing positron emission tomography (PET) ligands for imaging metabotropic glutamate receptor type 1 (mGluR1) is important for studying its role in the central nervous system. N-cyclohexyl-6-{[N-(2-methoxyethyl)-N-methylamino]methyl}-N-methylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-202074) exhibited high binding affinity for mGluR1 (K(i)=4.8 nM), and selectivity over other mGluRs in vitro. The purpose of this study was to label YM-202074 with carbon-11 and to evaluate in vitro and in vivo characteristics of [(11)C]YM-202074 as a PET ligand for mGluR1 in rodents. METHODS: [(11)C]YM-202074 was synthesized by N-[(11)C]methylation of its desmethyl precursor with [(11)C]methyl iodide. The in vitro and in vivo brain regional distributions were determined in rats using autoradiography and PET, respectively. RESULTS: [(11)C]YM-202074 (262-630 MBq, n=5) was obtained with radiochemical purity of >98% and specific activity of 27-52 GBq/mumol at the end of synthesis, starting from [(11)C]CO(2) of 19.3-21.5 GBq. In vitro autoradiographic results showed that the high specific binding of [(11)C]YM-202074 for mGluR1 was presented in the cerebellum, thalamus and hippocampus, which are known as mGluR1-rich regions. In ex vivo autoradiography and PET studies, the radioligand was specifically distributed in the cerebellum, although the uptake was low. Furthermore, the regional distribution was fairly uniform in the whole brain by pretreatment with JNJ16259685 (a mGluR1 antagonist). However, radiometabolite(s) was detected in the brain. CONCLUSIONS: From these results, especially considering the low brain uptake and the influx of radiometabolite(s) into brain, [(11)C]YM-202074 may not be a useful PET ligand for in vivo imaging of mGluR1 in the brain. Copyright 2010 Elsevier Inc. All rights reserved.
Authors: Rong Xu; Paolo Zanotti-Fregonara; Sami S Zoghbi; Robert L Gladding; Alicia E Woock; Robert B Innis; Victor W Pike Journal: J Med Chem Date: 2013-11-07 Impact factor: 7.446
Authors: Paolo Zanotti-Fregonara; Vanessa N Barth; Jeih-San Liow; Sami S Zoghbi; David T Clark; Emily Rhoads; Edward Siuda; Beverly A Heinz; Eric Nisenbaum; Bruce Dressman; Elizabeth Joshi; Debra Luffer-Atlas; Matthew J Fisher; John J Masters; Nancy Goebl; Steven L Kuklish; Cheryl Morse; Johannes Tauscher; Victor W Pike; Robert B Innis Journal: Eur J Nucl Med Mol Imaging Date: 2012-11-08 Impact factor: 9.236
Authors: Paolo Zanotti-Fregonara; Vanessa N Barth; Sami S Zoghbi; Jeih-San Liow; Eric Nisenbaum; Edward Siuda; Robert L Gladding; Denise Rallis-Frutos; Cheryl Morse; Johannes Tauscher; Victor W Pike; Robert B Innis Journal: EJNMMI Res Date: 2013-06-10 Impact factor: 3.138