Novel 18F-Labeled {kappa}-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates

Publication Date:
2018-01-03
Publisher:
The Society of Nuclear Medicine (SNM)
Print ISSN:
0022-3123
Topics:
Medicine
Published by:
http://www.snm.org/
_version_ 1836398729407496192
autor Li, S., Cai, Z., Zheng, M.-Q., Holden, D., Naganawa, M., Lin, S.-F., Ropchan, J., Labaree, D., Kapinos, M., Lara-Jaime, T., Navarro, A., Huang, Y.
beschreibung The -opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several 11 C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of 18 F-LY2459989 as the first 18 F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11 C-LY2459989. Methods: The novel radioligand 18 F-LY2459989 was synthesized by 18 F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time–activity curves and the calculation of binding parameters. Results: With the iodonium ylide precursor, 18 F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (〉99%), and mean molar activity (1,175 GBq/μmol; n = 6). In monkeys, 18 F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of 18 F-LY2459989 in vivo. Regional time–activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex 〉 insula 〉 caudate/putamen 〉 frontal cortex 〉 temporal cortex 〉 thalamus, consistent with the reported KOR distribution in the monkey brain. Conclusion: The evaluation of 18 F-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of 18 F-LY2459989 and 11 C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that 18 F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo.
citation_standardnr 6127890
datenlieferant ipn_articles
feed_id 9585
feed_publisher The Society of Nuclear Medicine (SNM)
feed_publisher_url http://www.snm.org/
insertion_date 2018-01-03
journalissn 0022-3123
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The Society of Nuclear Medicine (SNM)
quelle Journal of Nuclear Medicine
relation http://jnm.snmjournals.org/cgi/content/short/59/1/140?rss=1
search_space articles
shingle_author_1 Li, S., Cai, Z., Zheng, M.-Q., Holden, D., Naganawa, M., Lin, S.-F., Ropchan, J., Labaree, D., Kapinos, M., Lara-Jaime, T., Navarro, A., Huang, Y.
shingle_author_2 Li, S., Cai, Z., Zheng, M.-Q., Holden, D., Naganawa, M., Lin, S.-F., Ropchan, J., Labaree, D., Kapinos, M., Lara-Jaime, T., Navarro, A., Huang, Y.
shingle_author_3 Li, S., Cai, Z., Zheng, M.-Q., Holden, D., Naganawa, M., Lin, S.-F., Ropchan, J., Labaree, D., Kapinos, M., Lara-Jaime, T., Navarro, A., Huang, Y.
shingle_author_4 Li, S., Cai, Z., Zheng, M.-Q., Holden, D., Naganawa, M., Lin, S.-F., Ropchan, J., Labaree, D., Kapinos, M., Lara-Jaime, T., Navarro, A., Huang, Y.
shingle_catch_all_1 Novel 18F-Labeled {kappa}-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates
The -opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several 11 C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of 18 F-LY2459989 as the first 18 F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11 C-LY2459989. Methods: The novel radioligand 18 F-LY2459989 was synthesized by 18 F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time–activity curves and the calculation of binding parameters. Results: With the iodonium ylide precursor, 18 F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (>99%), and mean molar activity (1,175 GBq/μmol; n = 6). In monkeys, 18 F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of 18 F-LY2459989 in vivo. Regional time–activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex > insula > caudate/putamen > frontal cortex > temporal cortex > thalamus, consistent with the reported KOR distribution in the monkey brain. Conclusion: The evaluation of 18 F-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of 18 F-LY2459989 and 11 C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that 18 F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo.
Li, S., Cai, Z., Zheng, M.-Q., Holden, D., Naganawa, M., Lin, S.-F., Ropchan, J., Labaree, D., Kapinos, M., Lara-Jaime, T., Navarro, A., Huang, Y.
The Society of Nuclear Medicine (SNM)
0022-3123
00223123
shingle_catch_all_2 Novel 18F-Labeled {kappa}-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates
The -opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several 11 C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of 18 F-LY2459989 as the first 18 F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11 C-LY2459989. Methods: The novel radioligand 18 F-LY2459989 was synthesized by 18 F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time–activity curves and the calculation of binding parameters. Results: With the iodonium ylide precursor, 18 F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (>99%), and mean molar activity (1,175 GBq/μmol; n = 6). In monkeys, 18 F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of 18 F-LY2459989 in vivo. Regional time–activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex > insula > caudate/putamen > frontal cortex > temporal cortex > thalamus, consistent with the reported KOR distribution in the monkey brain. Conclusion: The evaluation of 18 F-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of 18 F-LY2459989 and 11 C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that 18 F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo.
Li, S., Cai, Z., Zheng, M.-Q., Holden, D., Naganawa, M., Lin, S.-F., Ropchan, J., Labaree, D., Kapinos, M., Lara-Jaime, T., Navarro, A., Huang, Y.
The Society of Nuclear Medicine (SNM)
0022-3123
00223123
shingle_catch_all_3 Novel 18F-Labeled {kappa}-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates
The -opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several 11 C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of 18 F-LY2459989 as the first 18 F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11 C-LY2459989. Methods: The novel radioligand 18 F-LY2459989 was synthesized by 18 F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time–activity curves and the calculation of binding parameters. Results: With the iodonium ylide precursor, 18 F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (>99%), and mean molar activity (1,175 GBq/μmol; n = 6). In monkeys, 18 F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of 18 F-LY2459989 in vivo. Regional time–activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex > insula > caudate/putamen > frontal cortex > temporal cortex > thalamus, consistent with the reported KOR distribution in the monkey brain. Conclusion: The evaluation of 18 F-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of 18 F-LY2459989 and 11 C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that 18 F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo.
Li, S., Cai, Z., Zheng, M.-Q., Holden, D., Naganawa, M., Lin, S.-F., Ropchan, J., Labaree, D., Kapinos, M., Lara-Jaime, T., Navarro, A., Huang, Y.
The Society of Nuclear Medicine (SNM)
0022-3123
00223123
shingle_catch_all_4 Novel 18F-Labeled {kappa}-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates
The -opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several 11 C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of 18 F-LY2459989 as the first 18 F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11 C-LY2459989. Methods: The novel radioligand 18 F-LY2459989 was synthesized by 18 F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time–activity curves and the calculation of binding parameters. Results: With the iodonium ylide precursor, 18 F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (>99%), and mean molar activity (1,175 GBq/μmol; n = 6). In monkeys, 18 F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of 18 F-LY2459989 in vivo. Regional time–activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex > insula > caudate/putamen > frontal cortex > temporal cortex > thalamus, consistent with the reported KOR distribution in the monkey brain. Conclusion: The evaluation of 18 F-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of 18 F-LY2459989 and 11 C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that 18 F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo.
Li, S., Cai, Z., Zheng, M.-Q., Holden, D., Naganawa, M., Lin, S.-F., Ropchan, J., Labaree, D., Kapinos, M., Lara-Jaime, T., Navarro, A., Huang, Y.
The Society of Nuclear Medicine (SNM)
0022-3123
00223123
shingle_title_1 Novel 18F-Labeled {kappa}-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates
shingle_title_2 Novel 18F-Labeled {kappa}-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates
shingle_title_3 Novel 18F-Labeled {kappa}-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates
shingle_title_4 Novel 18F-Labeled {kappa}-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates
timestamp 2025-06-30T23:31:42.877Z
titel Novel 18F-Labeled {kappa}-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates
titel_suche Novel 18F-Labeled {kappa}-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates
topic WW-YZ
uid ipn_articles_6127890