Dose-dependent effects of the CRF(1) receptor antagonist R317573 on regional brain activity in healthy male subjects.
BACKGROUND
Corticotropin-releasing factor receptor type 1 (CRF(1)) antagonists have been proposed as therapeutic agents in the treatment of mood and anxiety disorders although clinical evidence supporting their development and understanding of a dose-response relationship has been lacking.


METHODS
We tested two doses of the CRF(1) antagonist R317573 for effects on regional cerebral glucose metabolism (rCMglu) using [(18)F] fluoro-2-deoxy-D: -glucose (FDG) positron emission tomography (PET) following single-dose challenges in a double-blind, placebo-controlled, cross-over design, in 12 healthy male volunteers.


RESULTS
Single 30- and 200-mg doses of R317573 resulted in dose-related changes in rCMglu. Relative increases in rCMglu were observed in frontal cortical regions while relative decreases occurred in the putamen and right amygdala after both doses. Relative decreases occurred in cerebellum and right parahippocampal gyrus following the higher dose.


CONCLUSIONS
R317573 appears to produce acute dose-dependent changes in rCMglu. Effects occurred in regions that may be behaviorally relevant to mood and anxiety disorders. In some regions, these effects may be related to the receptor (target) density. Measuring acute effects on rCMglu with FDG-PET may offer a method for defining pharmacologically active doses for central nervous system targets for which selective radiotracers are lacking.
Schmidt
Mark E
ME
Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium. mschmid4@its.jnj.com
Andrews
Randolph D
RD
van der Ark
Peter
P
Brown
Terry
T
Mannaert
Erik
E
Steckler
Thomas
T
de Hoon
Jan
J
Van Laere
Koen
K
D000328:Adult; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D018592:Cross-Over Studies; D004307:Dose-Response Relationship, Radiation; D004311:Double-Blind Method; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D055815:Young Adult; D000099052:CRF Receptor, Type 1
D018019:Receptors, Corticotropin-Releasing Hormone; D019788:Fluorodeoxyglucose F18; D000099052:CRF Receptor, Type 1; D005947:Glucose