Abstract
Introduction: Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important secondary messengers in the central nervous system. Inhibition of PDE10A has been identified as a potential therapeutic target for treatment of various neuropsychiatric disorders. To assist the drug development program, we have identified a selective PDE10A PET tracer, [{sup 11}C]AMG 7980, for imaging PDE10A distribution using positron emission tomography. Methods: [{sup 11}C]AMG 7980 was prepared in a one-pot, two-step reaction. Dynamic PET scans were performed in non-human primates following a bolus or bolus plus constant infusion tracer injection paradigm. Regions-of-interest were defined on individuals’ MRIs and transferred to the co-registered PET images. Data were analyzed using Logan graphical analysis with metabolite-corrected input function, the simplified reference tissue model (SRTM) method and occupancy plots. A benchmark PDE10A inhibitor was used to demonstrate PDE10A-specific binding. Results: [{sup 11}C]AMG 7980 was prepared with a mean specific activity of 99 ± 74 GBq/μmol (n = 10) and a synthesis time of 45 min. Specific binding of the tracer was localized to the striatum and globus pallidus (GP) and low in other brain regions. Thalamus was used as the reference tissue to derive binding potentials (BP{sub ND}).
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Hwang, Dah-Ren;
[1]
Hu, Essa;
Rumfelt, Shannon;
[2]
Easwaramoorthy, Balu;
[3]
New York State Psychiatric Institute, NY (United States)];
Castrillon, John;
[4]
Davis, Carl;
[5]
Allen, Jennifer R.;
[2]
Chen, Hang;
[6]
Treanor, James;
[7]
Abi-Dargham, Anissa;
[3]
Department of Radiology, Columbia University, New York, NY (United States);
New York State Psychiatric Institute, NY (United States)];
Slifstein, Mark;
[3]
New York State Psychiatric Institute, NY (United States)]
- Department of Medical Sciences, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, California 91320–1799 (United States)
- Department of Small Molecule Chemistry, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, California 91320–1799 (United States)
- Department of Psychiatry, Columbia University, New York, NY (United States)
- New York State Psychiatric Institute, NY (United States)
- Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, California 91320–1799 (United States)
- Department of Neuroscience, Amgen Inc., South San Francisco, CA (United States)
- Department of Neuroscience, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, California 91320–1799 (United States)
Citation Formats
Hwang, Dah-Ren, Hu, Essa, Rumfelt, Shannon, Easwaramoorthy, Balu, New York State Psychiatric Institute, NY (United States)], Castrillon, John, Davis, Carl, Allen, Jennifer R., Chen, Hang, Treanor, James, Abi-Dargham, Anissa, Department of Radiology, Columbia University, New York, NY (United States), New York State Psychiatric Institute, NY (United States)], Slifstein, Mark, and New York State Psychiatric Institute, NY (United States)].
Initial characterization of a PDE10A selective positron emission tomography tracer [{sup 11}C]AMG 7980 in non-human primates.
United Kingdom: N. p.,
2014.
Web.
doi:10.1016/J.NUCMEDBIO.2014.01.007.
Hwang, Dah-Ren, Hu, Essa, Rumfelt, Shannon, Easwaramoorthy, Balu, New York State Psychiatric Institute, NY (United States)], Castrillon, John, Davis, Carl, Allen, Jennifer R., Chen, Hang, Treanor, James, Abi-Dargham, Anissa, Department of Radiology, Columbia University, New York, NY (United States), New York State Psychiatric Institute, NY (United States)], Slifstein, Mark, & New York State Psychiatric Institute, NY (United States)].
Initial characterization of a PDE10A selective positron emission tomography tracer [{sup 11}C]AMG 7980 in non-human primates.
United Kingdom.
https://doi.org/10.1016/J.NUCMEDBIO.2014.01.007
Hwang, Dah-Ren, Hu, Essa, Rumfelt, Shannon, Easwaramoorthy, Balu, New York State Psychiatric Institute, NY (United States)], Castrillon, John, Davis, Carl, Allen, Jennifer R., Chen, Hang, Treanor, James, Abi-Dargham, Anissa, Department of Radiology, Columbia University, New York, NY (United States), New York State Psychiatric Institute, NY (United States)], Slifstein, Mark, and New York State Psychiatric Institute, NY (United States)].
2014.
"Initial characterization of a PDE10A selective positron emission tomography tracer [{sup 11}C]AMG 7980 in non-human primates."
United Kingdom.
https://doi.org/10.1016/J.NUCMEDBIO.2014.01.007.
@misc{etde_22441196,
title = {Initial characterization of a PDE10A selective positron emission tomography tracer [{sup 11}C]AMG 7980 in non-human primates}
author = {Hwang, Dah-Ren, Hu, Essa, Rumfelt, Shannon, Easwaramoorthy, Balu, New York State Psychiatric Institute, NY (United States)], Castrillon, John, Davis, Carl, Allen, Jennifer R., Chen, Hang, Treanor, James, Abi-Dargham, Anissa, Department of Radiology, Columbia University, New York, NY (United States), New York State Psychiatric Institute, NY (United States)], Slifstein, Mark, and New York State Psychiatric Institute, NY (United States)]}
abstractNote = {Introduction: Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important secondary messengers in the central nervous system. Inhibition of PDE10A has been identified as a potential therapeutic target for treatment of various neuropsychiatric disorders. To assist the drug development program, we have identified a selective PDE10A PET tracer, [{sup 11}C]AMG 7980, for imaging PDE10A distribution using positron emission tomography. Methods: [{sup 11}C]AMG 7980 was prepared in a one-pot, two-step reaction. Dynamic PET scans were performed in non-human primates following a bolus or bolus plus constant infusion tracer injection paradigm. Regions-of-interest were defined on individuals’ MRIs and transferred to the co-registered PET images. Data were analyzed using Logan graphical analysis with metabolite-corrected input function, the simplified reference tissue model (SRTM) method and occupancy plots. A benchmark PDE10A inhibitor was used to demonstrate PDE10A-specific binding. Results: [{sup 11}C]AMG 7980 was prepared with a mean specific activity of 99 ± 74 GBq/μmol (n = 10) and a synthesis time of 45 min. Specific binding of the tracer was localized to the striatum and globus pallidus (GP) and low in other brain regions. Thalamus was used as the reference tissue to derive binding potentials (BP{sub ND}). The BP{sub ND} for caudate, putamen, and GP were 0.23, 0.65, 0.51, respectively by the graphical method, and 0.42, 0.76, and 0.75 from the SRTM method. A dose dependent decrease of BP{sub ND} was observed with the pre-treatment of a PDE10A inhibitor. A bolus plus infusion injection paradigm yielded similar results. Conclusion: [{sup 11}C]AMG 7980 has been successfully used for imaging PDE10A in non-human primate brain. Despite the fast brain kinetics it can be used to measure target occupancy of PDE10A inhibitors in non-human primates and potentially applicable to humans.}
doi = {10.1016/J.NUCMEDBIO.2014.01.007}
journal = []
issue = {4}
volume = {41}
journal type = {AC}
place = {United Kingdom}
year = {2014}
month = {Apr}
}
title = {Initial characterization of a PDE10A selective positron emission tomography tracer [{sup 11}C]AMG 7980 in non-human primates}
author = {Hwang, Dah-Ren, Hu, Essa, Rumfelt, Shannon, Easwaramoorthy, Balu, New York State Psychiatric Institute, NY (United States)], Castrillon, John, Davis, Carl, Allen, Jennifer R., Chen, Hang, Treanor, James, Abi-Dargham, Anissa, Department of Radiology, Columbia University, New York, NY (United States), New York State Psychiatric Institute, NY (United States)], Slifstein, Mark, and New York State Psychiatric Institute, NY (United States)]}
abstractNote = {Introduction: Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important secondary messengers in the central nervous system. Inhibition of PDE10A has been identified as a potential therapeutic target for treatment of various neuropsychiatric disorders. To assist the drug development program, we have identified a selective PDE10A PET tracer, [{sup 11}C]AMG 7980, for imaging PDE10A distribution using positron emission tomography. Methods: [{sup 11}C]AMG 7980 was prepared in a one-pot, two-step reaction. Dynamic PET scans were performed in non-human primates following a bolus or bolus plus constant infusion tracer injection paradigm. Regions-of-interest were defined on individuals’ MRIs and transferred to the co-registered PET images. Data were analyzed using Logan graphical analysis with metabolite-corrected input function, the simplified reference tissue model (SRTM) method and occupancy plots. A benchmark PDE10A inhibitor was used to demonstrate PDE10A-specific binding. Results: [{sup 11}C]AMG 7980 was prepared with a mean specific activity of 99 ± 74 GBq/μmol (n = 10) and a synthesis time of 45 min. Specific binding of the tracer was localized to the striatum and globus pallidus (GP) and low in other brain regions. Thalamus was used as the reference tissue to derive binding potentials (BP{sub ND}). The BP{sub ND} for caudate, putamen, and GP were 0.23, 0.65, 0.51, respectively by the graphical method, and 0.42, 0.76, and 0.75 from the SRTM method. A dose dependent decrease of BP{sub ND} was observed with the pre-treatment of a PDE10A inhibitor. A bolus plus infusion injection paradigm yielded similar results. Conclusion: [{sup 11}C]AMG 7980 has been successfully used for imaging PDE10A in non-human primate brain. Despite the fast brain kinetics it can be used to measure target occupancy of PDE10A inhibitors in non-human primates and potentially applicable to humans.}
doi = {10.1016/J.NUCMEDBIO.2014.01.007}
journal = []
issue = {4}
volume = {41}
journal type = {AC}
place = {United Kingdom}
year = {2014}
month = {Apr}
}