Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study

7Citations
Citations of this article
10Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [11C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (VT) from a two-tissue compartment model. The administration of GSK356278 reduced [11C](R)-rolipram whole brain VT by 17% at 3 h post-dose (p = 0.01) and by 4% at 8 h post-dose. The mean plasma Cmax was 42.3 ng/ml, leading to a PDE4 occupancy of 48% at Tmax. The in vivo affinity of GSK356278 was estimated as EC50 = 46 ± 3.6 ng/ml. We present the first report of a direct estimation of PDE4 blockade in the living human brain. In vivo affinity of GSK356278 for the PDE4, estimated in this early phase study, was combined with GSK356278 safety and tolerability data to decide on a therapeutic dose for future clinical development.

References Powered by Scopus

Imaging dopamine receptors in humans with [<sup>11</sup>C]-(+)-PHNO: Dissection of D3 signal and anatomy

352Citations
N/AReaders
Get full text

PDE4 inhibitors: Current status

309Citations
N/AReaders
Get full text

Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats

109Citations
N/AReaders
Get full text

Cited by Powered by Scopus

Recent developments in the management of Huntington's disease

24Citations
N/AReaders
Get full text

Emergency management of chlorine gas exposure–a systematic review

19Citations
N/AReaders
Get full text

Lessons learned from using fMRI in the early clinical development of a mu-opioid receptor antagonist for disorders of compulsive consumption

6Citations
N/AReaders
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

van der Aart, J., Salinas, C., Dimber, R., Pampols-Maso, S., Weekes, A. A., Tonkyn, J., … Rabiner, E. A. (2018). Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study. Journal of Cerebral Blood Flow and Metabolism, 38(11), 2033–2040. https://doi.org/10.1177/0271678X17720868

Readers' Seniority

Tooltip

Researcher 3

50%

Professor / Associate Prof. 2

33%

PhD / Post grad / Masters / Doc 1

17%

Readers' Discipline

Tooltip

Medicine and Dentistry 2

40%

Neuroscience 2

40%

Agricultural and Biological Sciences 1

20%

Save time finding and organizing research with Mendeley

Sign up for free