The overall goal of this proposal is to investigate the role of the histamine H1 receptors during arousal and sleep by quantitative imaging of these receptors in the living human brain using [11C]pyrilamine and positron emission tomography (PET). Histamine H1 receptors in the brain have been implicated in the control of the circadian rhythm of sleep and wakefulness; H1 antagonists decrease alertness, increase slow wave sleep, and reduce rapid eye movement sleep. Pyrilamine, a potent H1 antagonist, has been successfully used in numerous neurochemical studies of H1 receptors in-vitro and ex-vivo; until recently, however, no radioligand has existed for direct investigation of these receptors in the living human brain. [11C]pyrilamine has now been synthesized by us for quantitative imaging of the H1 receptors with PET. We propose to quantify the uptake and release of [11C]pyrilamine in the brain by the compartmental approach as well as by the noncompartmental method of factor analysis of dynamic image sequences. The rate of metabolism and the appearance of metabolites of the radioligand will be investigated in animal models. The kinetics, biodistribution and radiation dose of [11C]pyrilamine in the human body will be established. Next, we propose to investigate the intrasubject variance and the diurnal variance of [11C]pyrilamine binding. Finally we will investigate the effects of physiologic situations of alertness and sleep on the histamine H1 receptors. The results of these measurements will be used to test the hypothesis that in the human brain sleep and wakefulness are reflected in state changes of the histamine H1 receptors. They may give a runway for clarification of the involvement of these receptors in disturbances of sleep and circadian rhythm. Our work benefits from being carried out in the Division of Nuclear Medicine of the Johns Hopkins University, which has long been recognized for its neuroreceptor research with PET and possesses all the human and technical resources needed for this project.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS030597-02
Application #
3478528
Study Section
Neurology A Study Section (NEUA)
Project Start
1992-08-05
Project End
1997-07-31
Budget Start
1993-09-30
Budget End
1994-07-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218