Use of the H3 receptor antagonist radioligand [3H]-A-349821 to reveal in vivo receptor occupancy of cognition enhancing H3 receptor antagonists.
OBJECTIVE
The histamine H3 receptor antagonist radioligand [3H]-A-349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H3 receptor antagonists that affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H3 receptor occupancy to blood levels and efficacy in preclinical models.


METHODS
In vivo cerebral cortical H3 receptor occupancy by [3H]-A-349821 was determined in rats from differences in [3H]-A-349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H3 receptors. Comparisons were made to relate antagonist H3 receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five-trial inhibitory avoidance response in rat pups.


RESULTS
In adult rats, [3H]-A-349821, 1.5 microg x kg(-1), penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, [3H]-A-349821 levels were twofold higher in the latter. With increasing [3H]-A-349821 doses, cortical H3 receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer [3H]-A-349821 doses, ABT-239 and other H3 receptor antagonists inhibited H3 receptor occupancy by [3H]-A-349821 in a dose-dependent manner. Blood levels of the antagonists corresponding to H3 receptor occupancy were consistent with blood levels associated with efficacy in the five-trial inhibitory avoidance response.


CONCLUSIONS
When employed as an occupancy radiotracer, [3H]-A-349821 provided valid measurements of in vivo H3 receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H3 receptor antagonists.
Miller
T R
TR
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. thomas.r.miller@abbott.com
Milicic
I
I
Bauch
J
J
Du
J
J
Surber
B
B
Browman
K E
KE
Marsh
K
K
Cowart
M
M
Brioni
J D
JD
Esbenshade
T A
TA
D000818:Animals; D001345:Autoradiography; D001362:Avoidance Learning / Q000187:drug effects; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D054828:Histamine H3 Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D014018:Tissue Distribution; D014316:Tritium
C489829:A349821; D001713:Biphenyl Compounds; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3; D014316:Tritium