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A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: synthesis and preclinical characterization of [(18)F]SDM-16
PURPOSE: To quantify the synaptic vesicle glycoprotein 2A (SV2A) changes in the whole central nervous system (CNS) under pathophysiological conditions, a high affinity SV2A PET radiotracer with improved in vivo stability is desirable to minimize the potential confounding effect of radiometabolites....
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8940841/ https://www.ncbi.nlm.nih.gov/pubmed/34761284 http://dx.doi.org/10.1007/s00259-021-05597-5 |
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author | Zheng, Chao Holden, Daniel Zheng, Ming-Qiang Pracitto, Richard Wilcox, Kyle C. Lindemann, Marcel Felchner, Zachary Zhang, Li Tong, Jie Fowles, Krista Finnema, Sjoerd J. Nabulsi, Nabeel Carson, Richard E. Huang, Yiyun Cai, Zhengxin |
author_facet | Zheng, Chao Holden, Daniel Zheng, Ming-Qiang Pracitto, Richard Wilcox, Kyle C. Lindemann, Marcel Felchner, Zachary Zhang, Li Tong, Jie Fowles, Krista Finnema, Sjoerd J. Nabulsi, Nabeel Carson, Richard E. Huang, Yiyun Cai, Zhengxin |
author_sort | Zheng, Chao |
collection | PubMed |
description | PURPOSE: To quantify the synaptic vesicle glycoprotein 2A (SV2A) changes in the whole central nervous system (CNS) under pathophysiological conditions, a high affinity SV2A PET radiotracer with improved in vivo stability is desirable to minimize the potential confounding effect of radiometabolites. The aim of this study was to develop such a PET tracer based on the molecular scaffold of UCB-A, and evaluate its pharmacokinetics, in vivo stability, specific binding, and nonspecific binding signals in nonhuman primate brains, in comparison with [(11)C]UCB-A, [(11)C]UCB-J, and [(18)F]SynVesT-1. METHODS: The racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one) and its two enantiomers were synthesized and assayed for in vitro binding affinities to human SV2A. We synthesized the enantiopure [(18)F]SDM-16 using the corresponding enantiopure arylstannane precursor. Nonhuman primate brain PET scans were performed on FOCUS 220 scanners. Arterial blood was drawn for the measurement of plasma free fraction (f(P)), radiometabolite analysis, and construction of the plasma input function. Regional time-activity curves (TACs) were fitted with the one-tissue compartment (1TC) model to obtain the volume of distribution (V(T)). Nondisplaceable binding potential (BP(ND)) was calculated using either the nondisplaceable volume of distribution (V(ND)) or the centrum semiovale (CS) as the reference region. RESULTS: SDM-16 was synthesized in 3 steps with 44% overall yield and has the highest affinity (K(i) = 0.9 nM) to human SV2A among all reported SV2A ligands. [(18)F]SDM-16 was prepared in about 20% decay-corrected radiochemical yield within 90 min, with greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in monkey brains and was metabolically more stable than the other SV2A PET tracers. The f(P) of [(18)F]SDM-16 was 69%, which was higher than those of [(11)C]UCB-J (46%), [(18)F]SynVesT-1 (43%), [(18)F]SynVesT-2 (41%), and [(18)F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test–retest variability (TRV) was 7 ± 3%, and averaged absolute TRV (aTRV) was 14 ± 7% for the analyzed brain regions. CONCLUSION: We have successfully synthesized a novel SV2A PET tracer [(18)F]SDM-16, which has the highest SV2A binding affinity and metabolical stability among published SV2A PET tracers. The [(18)F]SDM-16 brain PET images showed superb contrast between gray matter and white matter. Moreover, [(18)F]SDM-16 showed high specific and reversible binding in the NHP brains, allowing for the reliable and sensitive quantification of SV2A, and has potential applications in the visualization and quantification of SV2A beyond the brain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-021-05597-5. |
format | Online Article Text |
id | pubmed-8940841 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-89408412022-04-07 A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: synthesis and preclinical characterization of [(18)F]SDM-16 Zheng, Chao Holden, Daniel Zheng, Ming-Qiang Pracitto, Richard Wilcox, Kyle C. Lindemann, Marcel Felchner, Zachary Zhang, Li Tong, Jie Fowles, Krista Finnema, Sjoerd J. Nabulsi, Nabeel Carson, Richard E. Huang, Yiyun Cai, Zhengxin Eur J Nucl Med Mol Imaging Original Article PURPOSE: To quantify the synaptic vesicle glycoprotein 2A (SV2A) changes in the whole central nervous system (CNS) under pathophysiological conditions, a high affinity SV2A PET radiotracer with improved in vivo stability is desirable to minimize the potential confounding effect of radiometabolites. The aim of this study was to develop such a PET tracer based on the molecular scaffold of UCB-A, and evaluate its pharmacokinetics, in vivo stability, specific binding, and nonspecific binding signals in nonhuman primate brains, in comparison with [(11)C]UCB-A, [(11)C]UCB-J, and [(18)F]SynVesT-1. METHODS: The racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one) and its two enantiomers were synthesized and assayed for in vitro binding affinities to human SV2A. We synthesized the enantiopure [(18)F]SDM-16 using the corresponding enantiopure arylstannane precursor. Nonhuman primate brain PET scans were performed on FOCUS 220 scanners. Arterial blood was drawn for the measurement of plasma free fraction (f(P)), radiometabolite analysis, and construction of the plasma input function. Regional time-activity curves (TACs) were fitted with the one-tissue compartment (1TC) model to obtain the volume of distribution (V(T)). Nondisplaceable binding potential (BP(ND)) was calculated using either the nondisplaceable volume of distribution (V(ND)) or the centrum semiovale (CS) as the reference region. RESULTS: SDM-16 was synthesized in 3 steps with 44% overall yield and has the highest affinity (K(i) = 0.9 nM) to human SV2A among all reported SV2A ligands. [(18)F]SDM-16 was prepared in about 20% decay-corrected radiochemical yield within 90 min, with greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in monkey brains and was metabolically more stable than the other SV2A PET tracers. The f(P) of [(18)F]SDM-16 was 69%, which was higher than those of [(11)C]UCB-J (46%), [(18)F]SynVesT-1 (43%), [(18)F]SynVesT-2 (41%), and [(18)F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test–retest variability (TRV) was 7 ± 3%, and averaged absolute TRV (aTRV) was 14 ± 7% for the analyzed brain regions. CONCLUSION: We have successfully synthesized a novel SV2A PET tracer [(18)F]SDM-16, which has the highest SV2A binding affinity and metabolical stability among published SV2A PET tracers. The [(18)F]SDM-16 brain PET images showed superb contrast between gray matter and white matter. Moreover, [(18)F]SDM-16 showed high specific and reversible binding in the NHP brains, allowing for the reliable and sensitive quantification of SV2A, and has potential applications in the visualization and quantification of SV2A beyond the brain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-021-05597-5. Springer Berlin Heidelberg 2021-11-11 2022 /pmc/articles/PMC8940841/ /pubmed/34761284 http://dx.doi.org/10.1007/s00259-021-05597-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Zheng, Chao Holden, Daniel Zheng, Ming-Qiang Pracitto, Richard Wilcox, Kyle C. Lindemann, Marcel Felchner, Zachary Zhang, Li Tong, Jie Fowles, Krista Finnema, Sjoerd J. Nabulsi, Nabeel Carson, Richard E. Huang, Yiyun Cai, Zhengxin A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: synthesis and preclinical characterization of [(18)F]SDM-16 |
title | A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: synthesis and preclinical characterization of [(18)F]SDM-16 |
title_full | A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: synthesis and preclinical characterization of [(18)F]SDM-16 |
title_fullStr | A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: synthesis and preclinical characterization of [(18)F]SDM-16 |
title_full_unstemmed | A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: synthesis and preclinical characterization of [(18)F]SDM-16 |
title_short | A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: synthesis and preclinical characterization of [(18)F]SDM-16 |
title_sort | metabolically stable pet tracer for imaging synaptic vesicle protein 2a: synthesis and preclinical characterization of [(18)f]sdm-16 |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8940841/ https://www.ncbi.nlm.nih.gov/pubmed/34761284 http://dx.doi.org/10.1007/s00259-021-05597-5 |
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