Dah-Ren Hwang1, Essa Hu2, Shannon Rumfelt2, Balu Easwaramoorthy3, John Castrillon4, Carl Davis5, Jennifer R Allen2, Hang Chen6, James Treanor7, Anissa Abi-Dargham8, Mark Slifstein3. 1. Department of Medical Sciences, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. Electronic address: dahh@amgen.com. 2. Department of Small Molecule Chemistry, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. 3. Department of Psychiatry, Columbia University, New York, NY, USA; New York State Psychiatric Institute, NY, USA. 4. New York State Psychiatric Institute, NY, USA. 5. Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. 6. Department of Neuroscience, Amgen Inc., South San Francisco, CA. 7. Department of Neuroscience, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. 8. Department of Psychiatry, Columbia University, New York, NY, USA; Department of Radiology, Columbia University, New York, NY, USA; New York State Psychiatric Institute, NY, USA.
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, [(11)C]AMG 7980, for imaging PDE10A distribution using positron emission tomography. METHODS: [(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: [(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 (BPND). The BPND 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 BPND was observed with the pre-treatment of a PDE10A inhibitor. A bolus plus infusion injection paradigm yielded similar results. CONCLUSION: [(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.
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, [(11)C]AMG 7980, for imaging PDE10A distribution using positron emission tomography. METHODS: [(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: [(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 (BPND). The BPND 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 BPND was observed with the pre-treatment of a PDE10A inhibitor. A bolus plus infusion injection paradigm yielded similar results. CONCLUSION: [(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.
Authors: Essa Hu; Ning Chen; Roxanne K Kunz; Dah-Ren Hwang; Klaus Michelsen; Carl Davis; Ji Ma; Jianxia Shi; Dianna Lester-Zeiner; Randall Hungate; James Treanor; Hang Chen; Jennifer R Allen Journal: ACS Med Chem Lett Date: 2016-05-19 Impact factor: 4.345
Authors: Shu-Fei Lin; David Labaree; Ming-Kai Chen; Daniel Holden; Jean-Dominique Gallezot; Michael Kapinos; Jo-Ku Teng; Soheila Najafzadeh; Christophe Plisson; Eugenii A Rabiner; Roger N Gunn; Richard E Carson; Yiyun Huang Journal: Synapse Date: 2014-12-11 Impact factor: 2.562
Authors: Eric D Hostetler; Hong Fan; Aniket D Joshi; Zhizhen Zeng; Waisi Eng; Liza Gantert; Marie Holahan; Xianjun Meng; Patricia Miller; Stacey O'Malley; Mona Purcell; Kerry Riffel; Cristian Salinas; Mangay Williams; Bennett Ma; Nicole Buist; Sean M Smith; Paul J Coleman; Christopher D Cox; Brock A Flores; Izzat T Raheem; Jacquelynn J Cook; Jeffrey L Evelhoch Journal: Mol Imaging Biol Date: 2016-08 Impact factor: 3.488