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A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram.
Mol Imaging Biol. 2018 08; 20(4):615-622.MI

Abstract

PURPOSE

Phosphodiesterase 4 (PDE4) inhibition in the brain has been reported to improve cognitive function in animal models. Therefore, PDE4 inhibitors are one of key targets potential for drug development. Investigation of brain PDE4 occupancy would help to understand the effects of PDE4 inhibition to cognitive functions. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor used clinically for severe chronic obstructive pulmonary disease, but the effects to the brain have not been well investigated. In this study, we aimed to investigate whether roflumilast entered the brain and occupied PDE4 in nonhuman primates.

PROCEDURES

Positron emission tomography (PET) measurements with (R)-[11C]rolipram were performed at baseline and after intravenous (i.v.) administration of roflumilast (3.6 to 200 μg/kg) in three female rhesus monkeys. Arterial blood samples were taken to obtain the input function. Protein binding was measured to obtain the free fraction (fp) of the radioligand. Total distribution volume (VT) and VT/fp were calculated as outcome measures from two tissue compartment model. Lassen plot approach was taken to estimate the target occupancy.

RESULTS

The brain uptake of (R)-[11C]rolipram decreased after roflumilast administration. PDE 4 occupancy by roflumilast showed dose- and plasma concentration-dependent increase, although PDE4 occupancy did not reach 50 % even after the administration of up to 200 μg/kg of roflumilast, regardless of outcome measures, VT or VT/fp.

CONCLUSIONS

This PET study showed that the brain PDE4 binding was blocked to a certain extent after i.v. administration of clinical relevant doses of roflumilast in nonhuman primates. Further clinical PET evaluation is needed to understand the relationship between PDE4 inhibition and potential improvement of cognitive function in human subjects.

Authors+Show Affiliations

Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden. akihiro.takano@ki.se.Takeda Development Center Americas, Inc., Deerfield, IL, 60015, USA.Takeda Development Center, London, UK. Orchard Therapeuitcs, Birchin Lane, London, UK.Takeda Development Center Americas, Inc., Deerfield, IL, 60015, USA. Eli Lilly and Company, Indianapolis, IN, USA.Takeda Development Center Americas, Inc., Deerfield, IL, 60015, USA.Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29441434

Citation

Takano, Akihiro, et al. "A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy By Roflumilast Using (R)-[11C]Rolipram." Molecular Imaging and Biology, vol. 20, no. 4, 2018, pp. 615-622.
Takano A, Uz T, Garcia-Segovia J, et al. A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram. Mol Imaging Biol. 2018;20(4):615-622.
Takano, A., Uz, T., Garcia-Segovia, J., Tsai, M., Lahu, G., Amini, N., Nakao, R., Jia, Z., & Halldin, C. (2018). A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram. Molecular Imaging and Biology, 20(4), 615-622. https://doi.org/10.1007/s11307-018-1168-0
Takano A, et al. A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy By Roflumilast Using (R)-[11C]Rolipram. Mol Imaging Biol. 2018;20(4):615-622. PubMed PMID: 29441434.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram. AU - Takano,Akihiro, AU - Uz,Tolga, AU - Garcia-Segovia,Jesus, AU - Tsai,Max, AU - Lahu,Gezim, AU - Amini,Nahid, AU - Nakao,Ryuji, AU - Jia,Zhisheng, AU - Halldin,Christer, PY - 2018/2/15/pubmed PY - 2019/3/1/medline PY - 2018/2/15/entrez KW - PDE4 KW - PET KW - Primate KW - Roflumilast SP - 615 EP - 622 JF - Molecular imaging and biology JO - Mol Imaging Biol VL - 20 IS - 4 N2 - PURPOSE: Phosphodiesterase 4 (PDE4) inhibition in the brain has been reported to improve cognitive function in animal models. Therefore, PDE4 inhibitors are one of key targets potential for drug development. Investigation of brain PDE4 occupancy would help to understand the effects of PDE4 inhibition to cognitive functions. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor used clinically for severe chronic obstructive pulmonary disease, but the effects to the brain have not been well investigated. In this study, we aimed to investigate whether roflumilast entered the brain and occupied PDE4 in nonhuman primates. PROCEDURES: Positron emission tomography (PET) measurements with (R)-[11C]rolipram were performed at baseline and after intravenous (i.v.) administration of roflumilast (3.6 to 200 μg/kg) in three female rhesus monkeys. Arterial blood samples were taken to obtain the input function. Protein binding was measured to obtain the free fraction (fp) of the radioligand. Total distribution volume (VT) and VT/fp were calculated as outcome measures from two tissue compartment model. Lassen plot approach was taken to estimate the target occupancy. RESULTS: The brain uptake of (R)-[11C]rolipram decreased after roflumilast administration. PDE 4 occupancy by roflumilast showed dose- and plasma concentration-dependent increase, although PDE4 occupancy did not reach 50 % even after the administration of up to 200 μg/kg of roflumilast, regardless of outcome measures, VT or VT/fp. CONCLUSIONS: This PET study showed that the brain PDE4 binding was blocked to a certain extent after i.v. administration of clinical relevant doses of roflumilast in nonhuman primates. Further clinical PET evaluation is needed to understand the relationship between PDE4 inhibition and potential improvement of cognitive function in human subjects. SN - 1860-2002 UR - https://www.unboundmedicine.com/medline/citation/29441434/A_Nonhuman_Primate_PET_Study:_Measurement_of_Brain_PDE4_Occupancy_by_Roflumilast_Using__R__[11C]Rolipram_ L2 - https://dx.doi.org/10.1007/s11307-018-1168-0 DB - PRIME DP - Unbound Medicine ER -