Synthesis and preclinical evaluation of carbon-11 labelled N-((5-(4-fluoro-2-[11C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine as a PET tracer for NR2B subunit-containing NMDA receptors |
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| Institution: | 1. Department of Environmental Toxicology, University of California, Davis, Davis, CA 95616, USA;2. California National Primate Research Center, University of California, Davis, Davis, CA 95616, USA;3. Division of Morphological Sciences and Biostatistics, Boonshoft School of Medicine, Wright State University, Dayton, OH 45434, USA;1. Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, Shandong, China;2. Key Laboratory of Radiation Oncology of Shandong Province, Shandong Cancer Hospital and Institute, Jinan, Shandong, China;3. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA;4. Department of Nuclear Medicine, Shandong Cancer Hospital and Institute, Jinan, Shandong, China;5. Department of Radiology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China;1. Laboratory for Radiopharmacy, KU Leuven, Belgium;2. MoSAIC, Molecular Small Animal Imaging Centre, KU Leuven, Belgium;3. Department of Nuclear Medicine & Molecular Imaging, University Medical Center Groningen, The Netherlands;4. Janssen Research & Development, Beerse, Belgium;5. Janssen Research & Development, Toledo, Spain;6. Division of Nuclear Medicine, KU Leuven and University Hospital Leuven, Belgium;1. Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan;2. Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan |
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| Abstract: | IntroductionThe N-methyl-D-Aspartate (NMDA) receptor plays an important role in learning and memory. Overactivation is thought to play an important role in neurodegenerative disorders such as Alzheimer's disease. Currently, it is not possible to assess N-methyl-D-aspartate receptor (NMDAr) bio-availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NR2B binding site of the NMDA receptor.MethodsN-((5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was radiolabelled with carbon-11 in the phenyl moiety. Biodistribution and blocking studies were carried out in anaesthetized mice and in non-anaesthetized rats.ResultsN-((5-(4-fluoro-2-11C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was prepared in 49 ± 3% (decay-corrected) yield, affording 4.1 ± 0.3 GBq of formulated product at the end of synthesis with a radiochemical purity of > 99% and with a specific activity of 78 ± 10 GBq/μmol.ConclusionA new NR2B PET ligand was developed in high yield. 11C]4 readily enters the brain and binds to the NR2B subunit-containing NMDAr in the rodent brain. High sigma-1 receptor binding may, however, limit its future application as a PET probe for imaging the NR2B subunit-containing NMDAr. Anaesthesia has an effect on NMDAr function and therefore can complicate interpretation of preclinical in vivo results. In addition, effects of endogenous compounds cannot be excluded. Despite these potential limitations, further studies are warranted to investigate the values of 11C]4 as an NR2B PET ligand. |
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