A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram

Akihiro Takano,Jesus Garcia-Segovia,Nahid Amini,Tolga Uz,Zhisheng Jia,Gezim Lahu,Christer Halldin,Ryuji Nakao,Max Tsai

doi:10.1007/s11307-018-1168-0

Abstract

PurposePhosphodiesterase 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.ProceduresPositron 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.ResultsThe 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.ConclusionsThis 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.

Highlights

The phosphodiesterase enzyme family plays a vital role for degrading cyclic nucleotides (cyclic adenosine monophosphate and cGMP) in the signal transduction pathway in all Takano A. et al.: Phosphodiesterase 4 (PDE4) Occupancy by Roflumilast cells
By preventing the cAMP hydrolysis, PDE4 inhibitors are considered to enhance intracellular signal transduction and increase the phosphorylation of cAMP response elementbinding protein (CREB), which enhances the transcription of proteins involved in synaptic plasticity and memory formation [7]
The degree of PDE4 inhibition which could be necessary to translate into improvements of cognitive domains has not been fully evaluated in vivo. It would be helpful for further understanding and development of PDE4 inhibitors to measure brain target occupancy using clinically available PDE4 inhibitors. In this positron emission tomography (PET) study, we aimed to investigate in nonhuman primates whether roflumilast entered the brain and demonstrated specific target occupancy of PDE4 using (R)-[11C]rolipram, a Positron emission tomography (PET) radioligand for PDE4 [14, 15]

Summary

Introduction

The phosphodiesterase enzyme family plays a vital role for degrading cyclic nucleotides (cyclic adenosine monophosphate (cAMP) and cGMP) in the signal transduction pathway in all Takano A. et al.: PDE4 Occupancy by Roflumilast cells. Roflumilast is the first PDE4 inhibitor to be approved for the treatment of severe chronic obstructive pulmonary disease [3]. Apremilast, another registered PDE4 inhibitor, has been introduced for the treatment of skin diseases such as psoriatic arthritis [4, 5]. By preventing the cAMP hydrolysis, PDE4 inhibitors are considered to enhance intracellular signal transduction and increase the phosphorylation of cAMP response elementbinding protein (CREB), which enhances the transcription of proteins involved in synaptic plasticity and memory formation [7]. Rolipram has been reported to improve cognitive function in animal models of cognitive impairment in neuropsychiatric and neurodegenerative diseases such as schizophrenia and Alzheimer’s disease [8,9,10,11,12,13]

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